To assess changes in muscle fat fraction (FF) and functional efficacy in patients with late-onset Pompe disease (LOPD) after long-term treatment with avalglucosidase alfa (AVA).

In the COMET trial of patients with late-onset Pompe disease, greater improvement in upright forced vital capacity (FVC) % predicted was observed with avalglucosidase alfa (AVA) vs alglucosidase alfa (ALGLU) (estimated treatment difference: 2.43%). The pre-specified mixed model repeated measures (MMRM) analysis demonstrated non-inferiority of AVA (P = 0.0074) and narrowly missed superiority (P = 0.063; 95% CI: –0.13–4.99). We report superiority of AVA in two post-hoc analyses that account for an extreme outlier participant with low FVC and severe chronic obstructive pulmonary disease at baseline: MMRM excluding the outlier (P = 0.013) and non-parametric analysis of all data with repeated measures analysis of covariance (P = 0.019).

S192or stabilization in individual items at Week 145 compared to starting with ALG and switching to AVA after the PAP.Switching from ALG to AVA resulted in an increase or maintenance in the proportion of patients reporting a ≥1-point increase or stabilization in 10 items: Supine: Neck Flexion, Hand Across Midline, Raises Extended Legs, Sit Up; Sit: Extending And Abducting Arms, Standing Up From Chair, Standing Up From Half Kneel, Picking Up An Object, Walking 10 m, and Jumping.Fewer items had more patients with a ≥1-point decrease following the switch: Prone: Raising The Torso; Supine: Hip And Knee Flexion, Squatting, Standing Up From Squat Position, Standing On One Leg, and Walking Up Steps.Overall, during 145 weeks, patients who started treatment on AVA continued to improve on 14/16 QMFT items (except Supine: Hand Across Midline; Sit: Extending And Abducting Arms) and patients who switched from ALG to AVA improved or stabilized on most items post-switch.These data demonstrate positive QMFT item response to AVA in more patients than to ALG.

Avalglucosidase alfa (AVAL) was approved in the United States (2021) for patients with late-onset Pompe disease (LOPD), aged ≥ 1 year. In the present study, pharmacokinetic (PK) simulations were conducted to propose alternative dosing regimens for pediatric LOPD patients based on a bodyweight cut-off. Population PK (PopPK) analysis was performed using nonlinear mixed effect modeling approach on pooled data from three clinical trials with LOPD patients, and a phase 2 study (NCT03019406) with infantile-onset Pompe disease (IOPD: 1–12 years) patients. A total of 2257 concentration-time points from 91 patients (LOPD, n = 75; IOPD, n = 16) were included in the analysis. The model was bodyweight dependent allometric scaling with time varying bodyweight included on clearance and distribution volume. Simulations were performed for two dosing regimens (20 mg/kg or 40 mg/kg) with different bodyweight cut-off (25, 30, 35 and 40 kg) by generating virtual pediatric (1–17 years) and adult patients. Corresponding simulated individual exposures (maximal concentration, C max and area under the curve in the 2-week dosing interval, AUC 2W ), and distributions were calculated. It was found that dosing of 40 mg/kg and 20 mg/kg in pediatric patients < 30 kg and ≥ 30 kg, respectively, achieved similar AVAL exposure (based on AUC 2W ) to adult patients receiving 20 mg/kg. PK simulations conducted on the basis of this model provided supporting data for the currently approved US labelling for dosing adapted bodyweight in LOPD patients ≥ 1 year by USFDA.

Background and Objectives Pompe 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. Methods NEO1 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. Results Twenty-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 <45 years at NEO1 enrollment in both the Naive and Switch Groups. Discussion Avalglucosidase 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 Evidence This 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 Information NCT01898364 (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.

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.

BackgroundThe objective of this article is to evaluate the pharmacokinetics, efficacy and safety of lixisenatide (subcutaneous injection) in elderly (65years old) and very elderly (75years old) patients with type 2 diabetes mellitus.MethodsWe conducted a phase I, single-centre, open-label study to evaluate the safety and pharmacokinetics of a single lixisenatide 20 mu g 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 mu g once daily or placebo.ResultsThe pharmacokinetics study included 36 healthy subjects, including 18 elderly healthy subjects (65years old) and 18 matched young healthy subjects (18-45years old). The pooled analysis included 3188 patients, including 2565 patients <65years old and 623 patients 65years old (including 79 patients 75years old). Mean exposure with lixisenatide 20 mu g was similar to 30% higher in elderly than in young subjects, and the terminal half-life was prolonged by similar to 1.6 times. Maximum concentration (C-max) and time to C-max (t(max)) were comparable in both groups. Equal numbers of elderly and young subjects reported treatment-emergent adverse events, the majority of which were gastrointestinal disorders. In the pooled analysis, lixisenatide 20 mu g once daily provided significant reductions in HbA(1c)versus placebo for all age groups. There was a similar incidence of treatment-emergent adverse events across all age groups (range: 69-73%). The incidence of symptomatic hypoglycaemia was generally comparable between lixisenatide-treated and placebo-treated patients.ConclusionThese data suggest that lixisenatide is effective and well tolerated in elderly and very elderly patients with type 2 diabetes mellitus. (c) 2014 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons, Ltd.

Introduction: Lixisenatide is a once-daily short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) used in the treatment of type 2 diabetes mellitus (T2DM). It is used in combination with oral antidiabetics and/or basal insulin in patients inadequately controlled on these medications and who are undergoing diet and lifestyle modification. GLP-1RAs glucose-dependently increase insulin secretion, decrease glucagon secretion, and slow gastric emptying, thereby improving glycemic control. GLP-1RAs are associated with body weight benefits and low rates of hypoglycemia which are welcome in patients with T2DM. Areas covered: The authors describe the identification of GLP-1RAs as suitable targets for modification with structure-inducing probe technology to improve stability and resistance to proteolytic degradation. Clinical studies have assessed lixisenatide across > 5000 patients as a monotherapy or add-on to a variety of commonly used antidiabetic medications. These studies highlighted the effects of lixisenatide on gastric emptying, explaining its particular improvements in postprandial plasma glucose (PPG) excursions and underscoring its efficacy in combination with insulin glargine. Lixisenatide was well tolerated, with nausea and vomiting being the most frequently reported adverse events. Expert opinion: The once-daily administration of lixisenatide as well as its substantial sustained effect on gastric emptying and, hence, PPG excursions are all important features compared with the other GLP-1RAs. The combination of two injectables, such as basal insulin to lower fasting plasma glucose and a GLP-1RA that curtails PPG excursions, is clinically valuable and could differentiate lixisenatide from other GLP-1RAs, especially from those continuously acting GLP-1RAs with little effect on gastric emptying and PPG excursions.

Aims: To assess efficacy and safety of lixisenatide once-daily versus placebo in Type 2 diabetes mellitus (T2DM) patients inadequately controlled on sulfonylurea (SU) +/- metformin.Methods: In this randomized, double-blind, two-arm, parallel-group, multicenter study, patients received lixisenatide 20 mu g once-daily or placebo for 24 weeks in a stepwise dose increase on top of SUs +/- metformin. Primary outcome was change in HbA(1c) from baseline to Week 24.Results: Lixisenatide provided a significant reduction in HbA(1c) at Week 24 versus placebo (LS mean: -0.85% vs. -0.10%; p < 0.0001) and more patients achieved HbA(1c) < 7.0% (36.4% vs. 13.5%; p < 0.0001). Lixisenatide significantly lowered FPG and body weight versus placebo. In breakfast meal test patients, lixisenatide reduced 2-hour PPG versus placebo (LS mean: -111.48 vs. -3.80 mg/dL [-6.19 vs. -0.21 mmol/L]; p < 0.0001) and glucose excursion (-94.11 vs. + 6.24 mg/dL [-5.22 vs. + 0.35 mmol/L]), and reduced 2-hour glucagon, insulin, proinsulin, and C-peptide. The percentage of AEs was 68.3% for lixisenatide and 61.1% for placebo; and for SAEs: 3.5% versus 5.6%, respectively. Lixisenatide did not significantly increase symptomatic hypoglycemia versus placebo (15.3% vs. 12.3%, respectively); one severe episode of hypoglycemia was reported with lixisenatide.Conclusions: Once-daily lixisenatide significantly improved glycemic control, with a pronounced postprandial effect, without significant increase in symptomatic/severe hypoglycemia risk and with weight loss over 24 weeks. (C) 2014 The Authors. Published by Elsevier Inc.

RESULTSdLixisenatide morning injection significantly reduced mean HbA1c versus combined placebo (mean change20.9% [9.8 mmol/mol] vs.20.4% [4.4 mmol/mol]; least squares [LS] mean difference vs. placebo20.5% [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 25.9 vs.21.4 mmol/L; LS mean difference 24.5 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.

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 <7.0%) and improvements in fasting plasma glucose were comparable. Both agents induced weight loss (from 94.5 to 91.7 kg and from 96.7 to 92.9 kg with lixisenatide and exenatide, respectively). Incidence of adverse events (AEs) was similar for lixisenatide and exenatide, as was incidence of serious AEs (2.8 and 2.2%, respectively). Discontinuations attributable to AEs occurred in 33 lixisenatide (10.4%) and 41 exenatide (13.0%) patients. In the lixisenatide group, fewer participants experienced symptomatic hypoglycemia (2.5 vs. 7.9%; P < 0.05), with fewer gastrointestinal events (especially nausea; 24.5 vs. 35.1%; P < 0.05). 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.

Le nombre de sujets âgés (SA) diabétiques de type 2 augmente avec l'espérance de vie et leur prise en charge peut s'avérer difficile. L'effet de l'âge sur la pharmacocinétique du lixisénatide a été évalué chez 18 SA (65–79 ans) et 18 jeunes (24–44 ans) sains. L'exposition moyenne après dose unique de 20 μg était ~ 30 % supérieure chez les SA par rapport aux jeunes et la demivie était prolongée de ~ 1,6 fois avec une Cmax et un tmax comparables. Le but de cette analyse était de comparer les variables cliniques du lixisénatide selon les classes d'âge au cours des essais cliniques de phase III. 612 SA ont reçu du lixisénatide au cours d'essais de phase II/III (567,9 patient-années) dont 59 sujets très âgés (STA) (≥ 75 ans) (58,3 patient-années). Cette analyse de 6 essais de phase III randomisés, contrôlés versus placebo a porté sur l'efficacité (HbA1c) et la tolérance (événements indésirables (EI), événements digestifs (ED), hypoglycémies) sous lixisénatide (20 μg/j) chez 379 SA incluant 48 STA (respectivement 436,5 et 49,1 patient-années) pendant 12 (GetGoal-Mono) ou 24 semaines (Get-Goal-M, -F1, -S, -L, -L-Asie). L'efficacité était identique quel que soit l'âge avec une baisse de l'HbA1c sous lixisénatide comparable chez les SA versus les < 65 ans dans les 6 études et significativement plus importante que sous placebo dans chaque classe d'âge. Dans une analyse poolée, la tolérance du lixisénatide était comparable à tout âge : EI et ED sous lixisénatide à 72 % et 43 % chez les SA vs 69 % et 41 % chez les < 65 ans et 73 % et 46 % chez les STA vs 69 % et 41 % chez les < 75 ans. L'incidence des hypoglycémies symptomatiques dépendait des traitements associés et était comparable au placebo quel que soit l'âge. Le lixisénatide est efficace et bien toléré chez les SA et STA.

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 <7.0% (53 mmol/mol) was attained by more lixisenatide (28%) than placebo (12%; P < 0.0001) participants. Lixisenatide reduced plasma glucose levels after a standardized breakfast (placebo-corrected reduction, –3.8 mmol/L; P < 0.0001); seven-point glucose profiles showed a reduction persisting through the day. Reductions in body weight (placebo corrected, –1.3 kg; P < 0.0001) and insulin dosage (–3.7 units/day; P = 0.012) were greater with lixisenatide. Main adverse events (AEs) with lixisenatide were gastrointestinal. Symptomatic hypoglycemia was 28% for lixisenatide and 22% for placebo; 4 of 328 subjects (1.2%) had severe hypoglycemia with lixisenatide vs. 0 of 167 with placebo. 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.