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Background: SAR341402 (SAR-Asp) is a biosimilar/follow-on of the originator insulin aspart-NovoLog®/NovoRapid® (NN-Asp). This study investigated whether the efficacy, safety, and immunogenicity findings for SAR-Asp versus NN-Asp, observed over 6 months in people with type 1 (n = 497) or type 2 diabetes (n = 100) treated with multiple daily injections in combination with insulin glargine (Lantus®), are maintained after 12 months. Materials and Methods: GEMELLI 1 was a multicenter, randomized, open-label, phase 3 study. Participants completing the initial 6-month treatment period continued on SAR-Asp or NN-Asp, as randomized, for a 6-month safety extension. Results: Of the 597 participants randomized, 264 out of 301 (87.7%) and 263 out of 296 (88.9%) assigned to SAR-Asp and NN-Asp, respectively, completed 12 months of treatment. Improved glycemic control was sustained at 12 months in both treatment groups, with similar least-squares mean reductions in glycated hemoglobin (HbA1c) from baseline (SAR-Asp: -0.25%; NN-Asp: -0.26%). Fasting plasma glucose and seven-point self-monitored plasma glucose profile changes, including postprandial glucose excursions, and changes in mealtime and basal insulin dosages were similar between groups. Safety and tolerability, including anti-insulin aspart antibodies (AIAs; incidence, prevalence, titers, cross-reactivity to human insulin), neutralizing antibodies (incidence, prevalence), hypoglycemia, and treatment-emergent adverse events (including hypersensitivity events and injection site reactions), were similar between groups. No relationship was observed between maximum individual AIA titers and change in HbA1c or insulin dose, hypoglycemia, or hypersensitivity reactions or between efficacy/safety measures and subgroups by presence or absence of treatment-emergent AIA. Conclusions: SAR-Asp and NN-Asp demonstrated similar efficacy and safety (including immunogenicity) in people with diabetes over 12 months of treatment.

Background and ObjectivesPompe disease is a rare, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase (GAA) and subsequent glycogen accumulation. Avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy designed for increased cellular uptake and glycogen clearance, has been studied for long-term efficacy and safety in patients with late-onset Pompe disease (LOPD). Here, we report up to 6.5 years' experience with avalglucosidase alfa during the NEO1 and NEO-EXT studies.MethodsNEO1 participants with LOPD, either treatment naive (Naive Group) or receiving alglucosidase alfa for ≥9 months (Switch Group), received avalglucosidase alfa (5, 10, or 20 mg/kg every other week [qow]) for 6 months before entering NEO-EXT and continued their NEO1 dose until all proceeded with 20 mg/kg qow. Safety and efficacy, a prespecified exploratory secondary outcome, were assessed; slopes of change for efficacy outcomes were calculated from a repeated mixed-measures model.ResultsTwenty-four participants enrolled in NEO1 (Naive Group, n = 10; Switch Group, n = 14); 21 completed and 19 entered NEO-EXT; in February 2020, 17 participants remained in NEO-EXT, with data up to 6.5 years. Avalglucosidase alfa was generally well tolerated during NEO-EXT, with a safety profile consistent with that in NEO1. No deaths or treatment-related life-threatening serious adverse events occurred. Eighteen participants developed antidrug antibodies without apparent effect on clinical outcomes. No participants who were tested developed immunoglobulin E antibodies. Upright forced vital capacity %predicted remained stable in most participants, with slope estimates (95% CIs) of −0.473 per year (−1.188 to 0.242) and −0.648 per year (−1.061 to −0.236) in the Naive and Switch Groups, respectively. Six-minute walk test (6MWT) %predicted was also stable for most participants, with slope estimates of −0.701 per year (−1.571 to 0.169) and −0.846 per year (−1.567 to −0.125) for the Naive and Switch Groups, respectively. Improvements in 6MWT distance were observed in most participants aged DiscussionAvalglucosidase alfa was generally well tolerated for up to 6.5 years in adult participants with LOPD either naive to alglucosidase alfa or who had previously received alglucosidase alfa for ≥9 months.Classification of EvidenceThis study provides Class IV evidence of long-term tolerability and sustained efficacy of avalglucosidase alfa in patients with LOPD after up to 6.5 years.Trial Registration InformationNCT01898364 (NEO1 first posted: July 12, 2013; clinicaltrials.gov/ct2/show/NCT01898364); NCT02032524 (NEO-EXT first posted: January 10, 2014; clinicaltrials.gov/ct2/show/NCT02032524). First participant enrollment: NEO1—August 19, 2013; NEO-EXT—February 27, 2014.

AimsTo assess efficacy and safety of lixisenatide once-daily versus placebo in Type 2 diabetes mellitus (T2DM) patients inadequately controlled on sulfonylurea (SU)±metformin.MethodsIn this randomized, double-blind, two-arm, parallel-group, multicenter study, patients received lixisenatide 20μg once-daily or placebo for 24 weeks in a stepwise dose increase on top of SUs±metformin. Primary outcome was change in HbA1c from baseline to Week 24.ResultsLixisenatide provided a significant reduction in HbA1c at Week 24 versus placebo (LS mean: −0.85% vs. −0.10%; p

OBJECTIVE To compare efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS Adults with diabetes inadequately controlled (HbA1c 7–10%) with metformin were randomized to lixisenatide 20 μg once daily (n = 318) or exenatide 10 μg twice daily (n = 316) in a 24-week (main period), open-label, parallel-group, multicenter study. The primary objective was a noninferiority assessment of lixisenatide versus exenatide in HbA1c change from baseline to week 24. RESULTS Lixisenatide once daily demonstrated noninferiority in HbA1c reduction versus exenatide twice daily. The least squares mean change was −0.79% (mean decrease 7.97 to 7.17%) for lixisenatide versus −0.96% (mean decrease 7.96 to 7.01%) for exenatide, and treatment difference was 0.17% (95% CI, 0.033–0.297), meeting a predefined noninferiority upper CI margin of 0.4%. Responder rate (HbA1c CONCLUSIONS Add-on lixisenatide once daily in type 2 diabetes inadequately controlled with metformin demonstrated noninferior improvements in HbA1c, with slightly lower mean weight loss, lower incidence of hypoglycemia, and better gastrointestinal tolerability compared with exenatide twice daily.

OBJECTIVE To examine the efficacy and safety of adding the once-daily glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated glycated hemoglobin (HbA1c). RESEARCH DESIGN AND METHODS We conducted a double-blind, parallel-group, placebo-controlled trial. Patients (n = 495) with established basal insulin therapy but inadequate glycemic control were randomized to add lixisenatide 20 μg or placebo for 24 weeks. Basal insulin dosage was unchanged except to limit hypoglycemia. HbA1c reduction from baseline was the primary end point. RESULTS Mean duration of diabetes was 12.5 years, duration of insulin use was 3.1 years, insulin dosage was 55 units/day, and baseline HbA1c was 8.4%. With lixisenatide, the placebo-corrected change of HbA1c from baseline was –0.4% (95% CI –0.6 to –0.2; P = 0.0002), and mean HbA1c at end point was 7.8%. HbA1c CONCLUSIONS By improving HbA1c and postprandial hyperglycemia without weight gain in type 2 diabetes with inadequate glycemic control despite stable basal insulin, lixisenatide may provide an alternative to rapid-acting insulin or other treatment options.

OBJECTIVE To examine the efficacy and safety of lixisenatide (20 μg once daily, administered before the morning or evening meal) as add-on therapy in patients with type 2 diabetes insufficiently controlled with metformin alone. RESEARCH DESIGN AND METHODS This was a 24-week, randomized, double-blind, placebo-controlled study in 680 patients with inadequately controlled type 2 diabetes (HbA1c 7–10% [53−86 mmol/mol]). Patients were randomized to lixisenatide morning (n = 255), lixisenatide evening (n = 255), placebo morning (n = 85), or placebo evening (n = 85) injections. RESULTS Lixisenatide morning injection significantly reduced mean HbA1c versus combined placebo (mean change −0.9% [9.8 mmol/mol] vs. −0.4% [4.4 mmol/mol]; least squares [LS] mean difference vs. placebo −0.5% [5.5 mmol/mol], P < 0.0001). HbA1c was significantly reduced by lixisenatide evening injection (mean change –0.8% [8.7 mmol/mol] vs. –0.4% [4.4 mmol/mol]; LS mean difference –0.4% [4.4 mmol/mol], P < 0.0001). Lixisenatide morning injection significantly reduced 2-h postprandial glucose versus morning placebo (mean change −5.9 vs. −1.4 mmol/L; LS mean difference −4.5 mmol/L, P < 0.0001). LS mean difference in fasting plasma glucose was significant in both morning (–0.9 mmol/L, P < 0.0001) and evening (–0.6 mmol/L, P = 0.0046) groups versus placebo. Mean body weight decreased to a similar extent in all groups. Rates of adverse events were 69.4% in both lixisenatide groups and 60.0% in the placebo group. Rates for nausea and vomiting were 22.7 and 9.4% for lixisenatide morning and 21.2 and 13.3% for lixisenatide evening versus 7.6 and 2.9% for placebo, respectively. Symptomatic hypoglycemia occurred in 6, 13, and 1 patient for lixisenatide morning, evening, and placebo, respectively, with no severe episodes. CONCLUSIONS In patients with type 2 diabetes inadequately controlled on metformin, lixisenatide 20 μg once daily administered in the morning or evening significantly improved glycemic control, with a pronounced postprandial effect, and was well tolerated.

OBJECTIVE To assess efficacy and safety of lixisenatide monotherapy in type 2 diabetes. RESEARCH DESIGN AND METHODS Randomized, double-blind, 12-week study of 361 patients not on glucose-lowering therapy (HbA1c 7–10%) allocated to one of four once-daily subcutaneous dose increase regimens: lixisenatide 2-step (10 μg for 1 week, 15 μg for 1 week, and then 20 μg; n = 120), lixisenatide 1-step (10 μg for 2 weeks and then 20 μg; n = 119), placebo 2-step (n = 61), or placebo 1-step (n = 61) (placebo groups were combined for analyses). Primary end point was HbA1c change from baseline to week 12. RESULTS Once-daily lixisenatide significantly improved HbA1c (mean baseline 8.0%) in both groups (least squares mean change vs. placebo: −0.54% for 2-step, −0.66% for 1-step; P < 0.0001). Significantly more lixisenatide patients achieved HbA1c CONCLUSIONS Once-daily lixisenatide monotherapy significantly improved glycemic control with a pronounced postprandial effect (75% reduction in glucose excursion) and was safe and well tolerated in type 2 diabetes.

Background The objective of this article is to evaluate the pharmacokinetics, efficacy and safety of lixisenatide (subcutaneous injection) in elderly (≥65 years old) and very elderly (≥75 years old) patients with type 2 diabetes mellitus. Methods We conducted a phase I, single-centre, open-label study to evaluate the safety and pharmacokinetics of a single lixisenatide 20 µg dose and a pooled analysis of six randomized, placebo-controlled, phase III studies (12-month or 24-month duration) that evaluated glycaemic parameters and safety in patients receiving lixisenatide 20 µg once daily or placebo. Results The pharmacokinetics study included 36 healthy subjects, including 18 elderly healthy subjects (≥65 years old) and 18 matched young healthy subjects (18–45 years old). The pooled analysis included 3188 patients, including 2565 patients

OBJECTIVE To examine the efficacy and safety of adding the once-daily glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated glycated hemoglobin (HbA1c). RESEARCH DESIGN AND METHODS We conducted a double-blind, parallel-group, placebo-controlled trial. Patients (n = 495) with established basal insulin therapy but inadequate glycemic control were randomized to add lixisenatide 20 μg or placebo for 24 weeks. Basal insulin dosage was unchanged except to limit hypoglycemia. HbA1c reduction from baseline was the primary end point. RESULTS Mean duration of diabetes was 12.5 years, duration of insulin use was 3.1 years, insulin dosage was 55 units/day, and baseline HbA1c was 8.4%. With lixisenatide, the placebo-corrected change of HbA1c from baseline was –0.4% (95% CI –0.6 to –0.2; P = 0.0002), and mean HbA1c at end point was 7.8%. HbA1c