Safety and Efficacy of Switching SAR341402 Insulin Aspart and Originator Insulin Aspart vs Continuous Use of Originator Insulin Aspart in Adults With Type 1 Diabetes: The GEMELLI X Trial.

BACKGROUND: SAR341402 insulin aspart (SAR-Asp) is a rapid-acting insulin analog developed as an interchangeable biosimilar to the marketed insulin aspart reference product (NovoLog; NN-Asp). GEMELLI X was a randomized controlled trial to assess outcomes with a biosimilar in line with the US Food and Drug Administration requirements for designation as an interchangeable biosimilar. This report assessed whether multiple switches between SAR-Asp and NN-Asp lead to equivalent safety and efficacy compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D) treated with multiple daily injections, using once-daily insulin glargine U100 (Lantus) as the basal insulin. METHODS: This open-label randomized (1:1), parallel-group, phase 3 trial compared four × four weeks of alternating use of individually titrated SAR-Asp and NN-Asp (NN-Asp for first four weeks, SAR-Asp in last four weeks; switching group) vs 16 weeks of continuous use of NN-Asp (nonswitching group). End points included pharmacokinetics, immunogenicity, adverse events, hypoglycemia, insulin dose, and change in efficacy parameters. RESULTS: Of the 210 patients randomized, 200 (95.5%) completed the trial. Patients assigned to switching group (n = 104) and nonswitching group (n = 106) showed similar safety and tolerability, including anti-insulin aspart antibody responses, adverse events, and hypoglycemia. At week 16, there was no relevant difference between switching vs nonswitching groups in the change from baseline in glycated hemoglobin (least square [LS] mean difference = 0.05% [95% confidence interval [CI] = -0.13, 0.22]; 0.50 mmol/mol [-1.40, 2.39]), fasting plasma glucose (LS mean difference = 0.23 mmol/L [95% CI = -1.08, 1.53]; 4.12 mg/dL [-19.38, 27.62]), and changes in insulin dosages. CONCLUSIONS: Alternating doses of SAR-Asp and NN-Asp compared with continuous use of NN-Asp showed similar safety, immunogenicity, and clinical efficacy in adults with T1D. This study supports interchangeability between SAR-Asp and NN-Asp in T1D management.

Pharmacokinetic similarity of switching SAR341402 insulin aspart biosimilar and NovoLog insulin aspart versus continuous use of NovoLog in adults with type 1 diabetes: The GEMELLI X trial.

AIM: To assess whether multiple switches between SAR341402 biosimilar insulin aspart (SAR-Asp) and the insulin aspart reference product (NovoLog; NN-Asp) leads to equivalent pharmacokinetic (PK) exposure compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D). MATERIALS AND METHODS: This multicentre, open-label, phase 3 study randomized (1:1) 210 subjects with T1D treated with once-daily insulin glargine U100 as basal insulin to four 4-week periods of alternating multiple daily injections of SAR-Asp and NN-Asp (NN-Asp for the first 4 weeks, SAR-Asp in the last 4 weeks; switching group) versus 16 weeks of continuous NN-Asp (non-switching group). At week 16, a single dose (0.15 U/kg) of SAR-Asp in the switching group (n = 95) or NN-Asp in the non-switching group (n = 105) was given in the morning before breakfast. Primary PK endpoints were area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax ) of SAR-Asp versus NN-Asp after the single dose at week 16. RESULTS: The extent of PK exposure was similar between the two treatments (SAR-Asp in the switching group and NN-Asp in the non-switching group) at week 16, with point estimates of treatment ratios close to 1. The 90% confidence intervals for AUC treatment ratios were contained within 0.8-1.25. For Cmax in the primary analysis set, the upper confidence limit was 1.32. This was because of the profiles of three participants with implausible high values. A prespecified sensitivity analysis excluding implausible values showed results contained within 0.8-1.25. CONCLUSIONS: PK exposure of SAR-Asp (switching group) and reference NN-Asp (non-switching group) were similar, supporting interchangeability between these two insulin aspart products.

Pharmacokinetics and Safety of iGlarLixi in Healthy Chinese Participants: Results of a Phase 1 Randomized Study.

INTRODUCTION: The Chinese Diabetes Society recommends basal insulin and glucagon-like peptide-1 receptor agonists as an add-on therapy to first-line oral antihyperglycemic drugs for people with type 2 diabetes (T2D). Fixed-ratio combination of insulin glargine 100 U/ml (iGlar) and lixisenatide (iGlarLixi) is known to improve glycemic control in adults with T2D. However, the pharmacokinetics of iGlarLixi has not been evaluated in Chinese participants. The present study evaluated pharmacokinetics and safety of two iGlarLixi (10 U/10 µg and 30 U/15 µg) doses following single subcutaneous administration in healthy Chinese participants. METHODS: This was a Phase 1, single-center, open-label, parallel-group, randomized study in healthy Chinese adults who were randomized to receive a single dose of iGlarLixi with either 1:1 (10 U/10 µg) or 2:1 (30 U/15 µg) ratio of iGlar and lixisenatide. Primary objectives include assessment of pharmacokinetics of iGlar in iGlarLixi 30 U/15 µg group and the pharmacokinetics of lixisenatide in both the groups (iGlarLixi 10 U/10 µg and iGlarLixi 30 U/15 µg). Safety and tolerability were also assessed. RESULTS: In iGlarLixi 30 U/15 µg group, iGlar concentrations were low and quantifiable in three of ten participants, while its main metabolite (M1) was quantifiable in all participants, reflecting rapid conversion of iGlar to M1. Median INS-tmax was 14.00 h for iGlar and 13.00 h post-dose for M1. Absorption of lixisenatide was similar in both dose groups with median tmax of 3.25 and 2.00 h post-dose in both groups. The exposure increase was dose proportionate with a 1.5-fold increase in the lixisenatide dose. Adverse events observed were consistent with those previously reported with iGlar or lixisenatide. CONCLUSION: iGlarLixi administration resulted in early absorption of both iGlar and lixisenatide with a good tolerability profile in healthy Chinese participants. These results are consistent with the previously published data from other geographic regions. TRIAL REGISTRATION: U1111-1194-9411.

Pharmacokinetic Similarity between Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 and Originator Insulin Aspart Mix 70/30 (NovoMix 30) in Indian Adults with Type 2 Diabetes: GEMELLI M Substudy.

Background: We compared the pharmacokinetic exposure, efficacy, safety and immunogenicity of biosimilar insulin aspart premix SAR341402 Mix 70/30 (SARAsp-Mix) with its originator NovoMix® 30 insulin aspart mix (NN-Mix) in adults with type 2 diabetes. Methods: This was a randomized, open-label, parallel-group, substudy of the phase 3 GEMELLI M trial performed in three Indian centres. Totally 13 Indian participants previously treated with premix insulin received a single subcutaneous 0.3 U/kg dose of each treatment and underwent pharmacokinetic sampling for 16 h after dosing. Participants were then treated for 26 weeks as per the main GEMELLI M trial with efficacy, safety and immunogenicity compared between groups. Results: The extent of exposure (area under the plasma concentration-time curve and maximum insulin aspart concentration) to SAR341402 insulin aspart in SARAsp-Mix and to insulin aspart in NN-Mix was similar following single doses of the allocated treatment. After 26 weeks, the mean ± SD [median] change in HbA1c from baseline was similar in both treatment groups (SARAsp-Mix -0.38% ± 1.54 [-1.00%]; NN-Mix -0.18% ± 1.97 [-0.80%]). Other efficacy endpoints, insulin dosages, anti-insulin aspart antibody response, hypoglycemia and adverse events were similar between groups. Conclusions: Our results support the findings from previous studies, that SARAsp-Mix has a similar pharmacokinetic profile to NN-Mix and provides effective glycemic control with similar safety and immunogenicity profile in Indian adults with type 2 diabetes.

A study on pharmacokinetics, pharmacodynamics and safety of lixisenatide in children and adolescents with type 2 diabetes.

OBJECTIVE: The aim of this study was to investigate the pharmacokinetic, pharmacodynamic and safety profile of the glucagon-like peptide-1 receptor agonist, lixisenatide, for the treatment of type 2 diabetes (T2D) in pediatric individuals. MATERIALS AND METHODS: In this Phase 1, multicenter, randomized, double-blind, placebo-controlled, parallel-group, ascending repeated dose study (NCT02803918), participants aged ≥10 and < 18 years were randomized 3:1 to receive once-daily lixisenatide in 2-week increments of 5, 10, and 20 µg (n = 18) or placebo (n = 5) for 6 weeks. RESULTS: Mean lixisenatide concentrations generally increased with increasing doses irrespective of anti-drug antibody (ADA) status; however, mean lixisenatide concentrations and inter-subject variability were higher for participants with positive ADA status. Improvements in fasting plasma glucose, post-prandial glucose, AUC0-4.5 , HbA1c , and body weight were observed with lixisenatide. Overall, the safety profile was consistent with the known profile in adults, with no unexpected side effects and no treatment-emergent adverse events resulting in death or discontinuation. The most common events in the lixisenatide group were vomiting (11.1%) and nausea (11.1%). No symptomatic hypoglycemia was reported in either group. No clinically significant hematologic, biochemical or vital sign abnormalities were observed. CONCLUSIONS: Mean lixisenatide concentrations generally increased with increasing dose, irrespective of ADA status. Lixisenatide was associated with improved glycemic control and a trend in body weight reduction compared with placebo. The safety and tolerability profile of repeated lixisenatide doses of up to 20 µg per day in children and adolescents with T2D was reflective of the established safety profile of lixisenatide in adults.

Similar Pharmacokinetics and Pharmacodynamics of Biosimilar SAR342434 Insulin Lispro and Japan-Approved Humalog Insulin Lispro in Healthy Japanese Subjects.

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.

Pharmacokinetic and pharmacodynamic similarity between SAR341402 insulin aspart and Japan-approved NovoRapid in healthy Japanese subjects.

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.

A single-dose euglycaemic clamp study in two cohorts to compare the exposure of SAR341402 (insulin aspart) Mix 70/30 with US- and European-approved versions of insulin aspart Mix 70/30 and SAR341402 rapid-acting solution in subjects with type 1 diabetes.

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 < .001) in early (0-4 hours) and intermediate (4-12 hours) exposure to SARAsp -Mix compared with SAR-Asp were observed, all exceeding a 20% difference. Pharmacodynamic results were in support of the pharmacokinetic findings for both cohorts. All treatments were well tolerated and there were no relevant differences in safety variables among treatments. CONCLUSIONS: SARAsp -Mix showed similar pharmacokinetic exposure to commercially available insulin aspart Mix 70/30 formulations, and a distinct exposure profile compared with SAR-Asp.

Single-Dose Euglycemic Clamp Study Demonstrating Pharmacokinetic and Pharmacodynamic Similarity Between SAR341402 Insulin Aspart and US- and EU-Approved Versions of Insulin Aspart in Subjects with Type 1 Diabetes.

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.

Impact of dose capping in insulin glargine/lixisenatide fixed-ratio combination trials in patients with type 2 diabetes.

OBJECTIVE: The LixiLan clinical trials of insulin glargine (iGlar)/lixisenatide fixed-ratio combination (iGlarLixi) investigated the safety and efficacy of iGlarLixi versus iGlar: LixiLan-O (NCT02058147) in patients with type 2 diabetes (T2D) inadequately controlled on oral antidiabetes drugs (OADs) and LixiLan-L (NCT02058160) in patients with T2D inadequately controlled on basal insulin ± OADs. In these two trials, both iGlar and iGlarLixi were titrated to a maximum (capped) dose of 60 units. We evaluated whether this may have affected the reported glycemic efficacy of iGlar, and the glycemic differences observed between treatment with iGlarLixi and iGlar. METHODS: The efficacy of iGlar under uncapped conditions was simulated in a two-step approach. First, a model characterizing the relationship between iGlar dose and fasting self-measured plasma glucose (f-SMPG) was developed. Then, the relationship between glycated hemoglobin A1c (A1C) and f-SMPG was established to translate simulated f-SMPG responses to A1C responses. RESULTS: Most patients achieved stable f-SMPG at ∼60 units/day, with no further reduction with increasing insulin dose. In comparisons of observed/capped and simulated/uncapped changes in mean A1C from baseline to Week 30, iGlarLixi consistently demonstrated treatment benefit compared with iGlar. Uncapping resulted in a slightly higher mean iGlar dose in both LixiLan-O (+0.72 units) and LixiLan-L (+2.1 units), without marked impact on f-SMPG or A1C change from baseline. CONCLUSION: Uncapping the iGlar dose in LixiLan-O and LixiLan-L would not have led to significant improvements in mean A1C reduction in the iGlar arm, supporting the conclusion that iGlarLixi provides additional, clinically relevant glycemic control versus iGlar alone.

Impact of lixisenatide dose range on clinical outcomes with fixed-ratio combination iGlarLixi in patients with type 2 diabetes.

OBJECTIVE: To evaluate the lixisenatide dose range delivered by the iGlarLixi SoloSTAR pen (5-20 µg), alone or in fixed-ratio combination with insulin glargine (iGlar; iGlarLixi). METHODS: Data from three clinical studies were analyzed to assess lixisenatide efficacy and safety: a phase 2a trial assessing gastric emptying effects (ACT6011); a phase 2b dose-ranging trial (DRI6012); and a randomized controlled phase 3 trial comparing iGlarLixi with its components of iGlar and lixisenatide (LixiLan-O). Efficacy metrics included glycated hemoglobin A1c (A1C), post-prandial glucose (PPG) values following a standardized breakfast, fasting plasma glucose (FPG), and weight change. Occurrence of gastrointestinal adverse events was also assessed. RESULTS: ACT6011: lixisenatide doses from 5-20 µg once daily (QD) suppressed PPG; maximal reductions in mean PPG area under the curve were achieved with doses ≥12.5 µg QD, but doses as low as 5 µg achieved 44% of maximal reduction. DRI6012: lixisenatide doses 5-20 µg QD resulted in significant, dose-dependent decreases in A1C, percentage of patients achieving A1C <7.0%, and 2-h PPG levels; doses of 20 µg achieved complete suppression of PPG. LixiLan-O: iGlarLixi decreased 2-h PPG across the entire dose range. Lixisenatide dose was unrelated to reductions in FPG with iGlarLixi. Similar reductions in A1C were seen with iGlarLixi across all lixisenatide doses. CONCLUSIONS: This analysis demonstrates the clinical benefit of lixisenatide alone or in the formulation of iGlarLixi over the entire dose range of lixisenatide contained in iGlarLixi (5-20 µg), supporting the selection of the lixisenatide dose range delivered by the iGlarLixi SoloSTAR pen.

6,8-Difluoro-4-methylumbiliferyl phosphate: a fluorogenic substrate for protein tyrosine phosphatases.

The fluorogenic substrate 6,8-difluoro-4-methylumbiliferyl phosphate (DIFMUP) has been widely used for the detection of serine and threonine phosphatase activities. Here we describe the use of this substrate for the characterization of protein tyrosine phosphatases (PTPs) and for the screening for PTP inhibitors. The measured kinetic and inhibitor constants for DIFMUP cleavage were comparable with those of the widely used but less discriminative and practicable substrates, para-nitrophenylphosphate and phosphotyrosine-containing peptides, respectively. Furthermore, the continuous and highly sensitive assay allows fast and accurate investigations of the type, kinetic behavior, and binding mode of small-molecule inhibitors. We discuss the validation of this assay system for various PTPs and its use in inhibitor screening for PTP1B.

Identification of beta-subunit of bacterial RNA-polymerase--a non-species-specific bacterial protein--as target of antibodies in primary biliary cirrhosis.

Several observations suggest that bacteria induce autoimmunity in primary biliary cirrhosis (PBC). Since no PBC-specific bacterial species could be identified, it can be speculated that the triggers are non-species-specific bacterial proteins. This hypothesis would imply that several or even all bacterial species can trigger PBC. Therefore, we investigated whether PBC exhibits immune reactions to non-species-specific bacterial antigens. Yersinia enterocolitica O3 was screened for the presence of proteins that were labeled by immunoblotting using PBC sera. We focused our investigations on a 160-kDa protein, which was further enriched and characterized by partial N-terminal amino acid sequencing. The prevalence of antibodies to this protein was determined by immunoblotting in a variety of diseases. The 160-kDa protein was identified as the beta-subunit of bacterial RNA-polymerase, a highly conserved bacterial protein with a very high degree of sequence identity among all bacterial species. Antibodies to the beta-subunit of bacterial RNA polymerase were specific for this protein. Until now no mammalian protein could be found that cross-reacts with these antibodies. The prevalence of antibodies to the beta-subunit of bacterial RNA polymerase (ARPA) using the protein from Yersinia enterocolitica O3 (serum dilution 1:1000) was: healthy controls (HC, N = 101) 7.9%, primary biliary cirrhosis (PBC, N = 61) 32.8%, autoimmune hepatitis type 1 (AIH, N = 46) 26.1%, alcoholic liver cirrhosis (ALC, N = 44) 9.1%, Crohn's disease (CD, N = 38) 7.9%, ulcerative colitis (UC, N = 24) 8.3%, primary sclerosing cholangitis + UC (PSC/UC, N = 11) 0%, acute yersiniosis (Yers, N = 36) 19.4%, acute infection with Campylobacter jejuni (Camp, N = 10) 0%, acute Q-fever (QF, N = 16) 6.25%, chronic hepatitis C (HCV, N = 39) 7.7%, c-ANCA-positive vasculitis (Vasc, N = 40) 15%, systemic lupus erythematosus (SLE, N = 28) 10.7%, and malaria tropica (MT, N = 24) 16.7%. There was no significant difference between PBC and AIH. The group of autoimmune liver diseases (PBC + AIH, N = 107, 29.9%) differed highly significantly from HC, chronic inflammatory bowel diseases (CD + UC + PSC/UC, N = 73, 6.8%), ALC, and HCV and also differed significantly (P = 0.01) from the group with bacterial and parasitic diseases (Yers + Camp + QF + MT, N = 86,13.95%) and from the group with Vasc + SLE (N = 68,13.2%). Testing of ARPA using the protein from E. coli yielded nearly identical results. In conclusion, an increased prevalence of antibodies to the beta-subunit of bacterial RNA polymerase, a highly conserved non-species-specific bacterial protein, can be found in primary biliary cirrhosis, but also in autoimmune hepatitis type I. These findings do not add an argument for a bacterial trigger of PBC. Rather, they suggest that ARPA belong to the pool of natural antibodies that are up-regulated in autoimmune liver diseases.