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.

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.

Regulatory Issues of Platform Trials: Learnings from EU-PEARL.

Although platform trials have many benefits, the complexity of these designs may result not only in increased methodological but also regulatory and ethical challenges. These aspects were addressed as part of the IMI project EU Patient-Centric Clinical Trial Platforms (EU-PEARL). We reviewed the available guidelines on platform trials in the European Union and the United States. This is supported and complemented by feedback received from regulatory interactions with the European Medicines Agency and the US Food and Drug Administration. Throughout the project we collected the needs of all relevant stakeholders including ethics committees, regulators, and health technology assessment bodies through active dialog and dedicated stakeholder workshops. Furthermore, we focused on methodological aspects and where applicable identified the corresponding guidance. Learnings from the guideline review, regulatory interactions, and workshops are provided. Based on these, a master protocol template was developed. Issues that still need harmonization or clarification in guidelines or where further methodological research is needed are also presented. These include questions around clinical trial submissions in Europe, the need for multiplicity control across the whole master protocol, the use of non-concurrent controls, and the impact of different randomization schemes. Master protocols are an efficient and patient-centered clinical trial design that can expedite drug development. However, they can also introduce additional operational and regulatory complexities. It is important to understand the different requirements of stakeholders upfront and address them in the trial. While relevant guidance is increasing, early dialog with relevant stakeholders can help to further support such designs.

Efficacy, Safety, and Immunogenicity of Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 Compared with Originator Insulin Aspart Mix 70/30 in Adults with Diabetes (GEMELLI M): A Subgroup Analysis by Prior Type of Premix Insulin.

INTRODUCTION: We compared the efficacy, safety, and immunogenicity of biosimilar insulin aspart premix SAR341402 Mix 70/30 (70% intermediate SAR341402 protamine and 30% rapid SAR341402 solution) (SARAsp-Mix) with its originator NovoMix 30 insulin aspart mix (NN-Mix) in adults with type 1 or type 2 diabetes switching from different premix insulin analogs. METHODS: This phase 3, randomized, open-label, multinational, 26-week trial (GEMELLI M) enrolled 402 participants with type 1 or type 2 diabetes. At randomization, participants switched from their prestudy premix insulin NovoMix 30 (n = 341) or Humalog Mix 25/Liprolog Mix 25 (n = 61) to equivalent (1:1) doses of either SARAsp-Mix or NN-Mix at least twice daily (1:1 randomization). In this subgroup analysis, efficacy measures [change in hemoglobin A1c (HbA1c), daily insulin dose], and safety outcomes [hypoglycemia incidence, adverse events (including hypersensitivity and injection site reactions), anti-insulin aspart antibodies] of SARAsp-Mix were compared with those of NN-Mix separately according to the participants' prestudy premix insulin. RESULTS: At week 26, change from baseline in HbA1c (primary efficacy endpoint) was similar between SARAsp-Mix and NN-Mix in those participants pretreated with NovoMix 30 [least squares (LS) mean difference 0.05%, 95% confidence interval (CI) -0.195% to 0.289%] or Humalog Mix 25/Liprolog Mix 25 (LS mean difference 0.28%, 95% CI -0.279% to 0.830%) (P value for treatment-by-subgroup interaction = 0.46). In both subgroups, safety outcomes, including immunogenicity, and changes in daily insulin doses were similar between treatments over 26 weeks. CONCLUSIONS: Efficacy, safety, and immunogenicity profiles of SARAsp-Mix are similar to NN-Mix over 26 weeks in adults with diabetes irrespective of prior type of premix insulin. TRIAL REGISTRATION: EudraCT number 2017-000092-84.

Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 Versus Originator Insulin Aspart Mix 70/30 (NovoMix 30) in People with Diabetes: A 26-Week, Randomized, Open-Label Trial (GEMELLI M).

INTRODUCTION: This study compared the efficacy, safety, and immunogenicity of biosimilar insulin aspart premix SAR341402 Mix 70/30 (SARAsp-Mix) with European-approved insulin aspart mix 70/30 - NovoMix® 30 (NN-Mix) in people with type 1 (T1D) or type 2 diabetes (T2D). METHODS: This 26-week, open-label, phase 3 trial enrolled 402 people with T1D (n = 105) or T2D (n = 297) previously treated with premix insulin, who were randomized (1:1) to SARAsp-Mix (n = 204) or NN-Mix (n = 198). RESULTS: After 26 weeks, the least squares (LS) mean [median] change in HbA1c from baseline was similar in both treatment groups (SARAsp-Mix - 0.55% [- 0.60%]; NN-Mix - 0.64% [- 0.60%]). The LS mean difference for SARAsp-Mix versus NN-Mix was 0.08%, with the upper bound of the two-sided 95% confidence interval (- 0.139 to 0.303) slightly above the prespecified noninferiority margin of 0.3%. Noninferiority of SARAsp-Mix over NN-Mix was not demonstrated in the primary intent-to-treat analysis, primarily because of one extreme outlying value impacted by the COVID-19 pandemic in the SARAsp-Mix group. Noninferiority was achieved in all secondary analyses, including prespecified per-protocol supportive and COVID-19 sensitivity analyses, as well as post hoc sensitivity analyses. Other efficacy endpoints, insulin dosages, anti-insulin aspart antibody response, hypoglycemia, and adverse events were similar between groups. CONCLUSIONS: The totality of evidence indicates that SARAsp-Mix provides effective glycemic control with a similar safety and immunogenicity profile to NN-Mix in people with diabetes treated for 26 weeks. TRIAL REGISTRATION: EudraCT number 2017-000092-84.

Efficacy, Safety, and Immunogenicity of Insulin Aspart Biosimilar SAR341402 Compared with Originator Insulin Aspart in Adults with Diabetes (GEMELLI 1): A Subgroup Analysis by Prior Type of Mealtime Insulin.

INTRODUCTION: The biosimilar SAR341402 insulin aspart (SAR-Asp) was compared to its originator NovoLog®/NovoRapid® insulin aspart (NN-Asp) in terms of efficacy, safety, and immunogenicity, in adults with type 1 or type 2 diabetes switching from different rapid-acting insulin analogs. METHODS: This phase 3, randomized, open-label, multinational, 52-week study (GEMELLI 1) enrolled participants with type 1 or type 2 diabetes (n = 597). At randomization, participants transitioned from NovoLog/NovoRapid (n = 380) or Humalog®/Liprolog® (n = 217) to equivalent (1:1) doses (or a dose at the discretion of the investigator) of either SAR-Asp or NN-Asp (1:1 randomization). Participants were treated with multiple daily injections in combination with insulin glargine 100 U/mL (Lantus®). In this subgroup analysis, efficacy measures (change in hemoglobin A1c [HbA1c], insulin dose [total, basal and mealtime]), and safety outcomes (hypoglycemia incidence, adverse events, anti-insulin aspart antibodies) of SAR-Asp were compared with those of NN-Asp separately according to the participants' prestudy mealtime insulin. RESULTS: At week 26 (primary efficacy endpoint), change in HbA1c was similar between SAR-Asp and NN-Asp in those participants pre-treated with NovoLog/NovoRapid (least squares [LS] mean difference - 0.04%, 95% confidence interval [CI] - 0.182 to 0.106%) or Humalog/Liprolog (LS mean difference - 0.15%, 95% CI - 0.336 to 0.043%) (P value for treatment by subgroup interaction = 0.36). This HbA1c response persisted over the 52 weeks of the study similarly for both treatments within each subgroup. In both subgroups, changes in insulin doses were similar between treatments over 26 weeks and 52 weeks, as were the incidences of severe or any hypoglycemia, adverse events (including hypersensitivity and injection site reactions), and anti-insulin aspart antibodies. CONCLUSIONS: Efficacy and safety (including immunogenicity) profiles of SAR-Asp are similar to those of NN-Asp over 52 weeks in adults with diabetes irrespective of prior type of mealtime insulin. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03211858.

Mean annual temperature influences local fine root proliferation and arbuscular mycorrhizal colonization in a tropical wet forest.

Mean annual temperature (MAT) is an influential climate factor affecting the bioavailability of growth-limiting nutrients nitrogen (N) and phosphorus (P). In tropical montane wet forests, warmer MAT drives higher N bioavailability, while patterns of P availability are inconsistent across MAT. Two important nutrient acquisition strategies, fine root proliferation into bulk soil and root association with arbuscular mycorrhizal fungi, are dependent on C availability to the plant via primary production. The case study presented here tests whether variation in bulk soil N bioavailability across a tropical montane wet forest elevation gradient (5.2°C MAT range) influences (a) morphology fine root proliferation into soil patches with elevated N, P, and N+P relative to background soil and (b) arbuscular mycorrhizal fungal (AMF) colonization of fine roots in patches. We created a fully factorial fertilized root ingrowth core design (N, P, N+P, unfertilized control) representing soil patches with elevated N and P bioavailability relative to background bulk soil. Our results show that percent AMF colonization of roots increased with MAT (r 2 = .19, p = .004), but did not respond to fertilization treatments. Fine root length (FRL), a proxy for root foraging, increased with MAT in N+P-fertilized patches only (p = .02), while other fine root morphological parameters did not respond to the gradient or fertilized patches. We conclude that in N-rich, fine root elongation into areas with elevated N and P declines while AMF abundance increases with MAT. These results indicate a tradeoff between P acquisition strategies occurring with changing N bioavailability, which may be influenced by higher C availability with warmer MAT.

Safety and Tolerability of Insulin Aspart Biosimilar SAR341402 Versus Originator Insulin Aspart (NovoLog) When Used in Insulin Pumps in Adults with Type 1 Diabetes: A Randomized, Open-Label Clinical Trial.

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.

Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 2 Diabetes, Also Using Insulin Glargine: SORELLA 2 Study.

BACKGROUND: SAR342434 (SAR-Lis) is a biosimilar (follow-on) of insulin lispro (U100; Humalog®; Ly-Lis). This study aimed to show similar efficacy, safety, and immunogenicity of SAR-Lis versus Ly-Lis in adult patients with type 2 diabetes mellitus (T2DM) treated with multiple daily injections, while using insulin glargine (GLA-100; Lantus®) as basal insulin. METHODS: SORELLA 2 was a 6-month, randomized, open-label, Phase 3 study (NCT02294474). Insulin doses were adjusted to achieve fasting and 2-h postprandial glucose targets according to American Diabetes Association guidelines. Primary endpoint was the HbA1c change from baseline to week 26 (tested for noninferiority of SAR-Lis vs. Ly-Lis with a margin of 0.3%). Secondary endpoints included fasting plasma glucose (FPG), seven-point self-monitored plasma glucose (SMPG) profiles, hypoglycemic events, treatment-emergent adverse events (TEAEs), and anti-insulin antibodies (AIA). RESULTS: A total of 505 patients were randomized (1:1) to multiple daily injections of SAR-Lis (n = 253) or Ly-Lis (n = 252) plus once-daily GLA-100. Least square (LS) mean (standard error) change in HbA1c from baseline to week 26 was similar in both treatment groups (SAR-Lis, -0.92% [0.051] and Ly-Lis, -0.85% [0.051]). Noninferiority at prespecified 0.3% noninferiority margin was demonstrated (LS mean difference of SAR-Lis vs. Ly-Lis: -0.07% [95% CI: -0.215 to 0.067]) as was inverse noninferiority. Similar changes in FPG, seven-point SMPG profiles, including postprandial glucose excursions and mean glucose over 24 h, and insulin dosages were observed in the two groups. Hypoglycemia, TEAEs, and AIA (incidence and prevalence) did not differ between groups. CONCLUSIONS: Results from this controlled study in patients with T2DM also using GLA-100 support similar efficacy and safety (including immunogenicity) of SAR-Lis and Ly-Lis.

Safety of Insulin Lispro and a Biosimilar Insulin Lispro When Administered Through an Insulin Pump.

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.

Anti-Insulin Antibodies and Adverse Events with Biosimilar Insulin Lispro Compared with Humalog Insulin Lispro in People with Diabetes.

BACKGROUND: SAR342434 (SAR-Lis) is a biosimilar (follow-on) of insulin lispro (Humalog®; Ly-Lis). Two randomized, controlled, open-label, parallel-group, phase 3 studies were conducted to compare the efficacy and safety of SAR-Lis and Ly-Lis, both in combination with insulin glargine (Lantus®). SORELLA 1 was a 12-month study in 507 people with type 1 diabetes mellitus (T1DM); SORELLA 2 was a 6-month study in 505 people with type 2 diabetes mellitus (T2DM). In this study, the impact of anti-insulin antibodies (AIA) to SAR-Lis and Ly-Lis on safety and glycemic control is reported. METHODS: AIA were measured regularly throughout both studies at a centralized laboratory blinded to treatment groups using a drug-specific AIA assay. The AIA status (positive or negative), AIA titers, and cross-reactivity to human insulin, insulin glargine, and insulin glargine metabolite M1 were analyzed. The potential effect of AIA on safety, particularly as related to hypersensitivity reactions, hypoglycemia, and treatment-emergent adverse events, as well as on glycemic control (HbA1c, insulin dose), was evaluated. RESULTS: AIA positive status at baseline was similar for the two insulins, but higher in T1DM than in T2DM. In both studies, the percentage of people newly developing AIA in the two treatment groups, or having a ≥4-fold increase in AIA titers, did not differ. 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. Hypersensitivity events and events adjudicated as allergic reactions were few and did not differ between the two groups. CONCLUSION: Insulin lispro SAR342434 and the originator insulin lispro had a similar immunogenicity profile in people with T1DM or T2DM.

Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 1 Diabetes Also Using Insulin Glargine-SORELLA 1 Study.

BACKGROUND: SAR342434 is a biosimilar follow-on of insulin lispro-Humalog®. This study aimed to show similar efficacy, safety, and immunogenicity of SAR342434 (SAR-Lis) versus insulin lispro-Humalog (Ly-Lis) in adult patients with type 1 diabetes (T1DM) treated with multiple daily injections while using basal insulin glargine (Lantus®; GLA-100). MATERIALS AND METHODS: SORELLA-1 was a randomized, open-label phase 3 study (NCT02273180). Patients completing the 6-month main study continued on SAR-Lis or Ly-Lis, as randomized, for a 6-month safety extension. Assessments included change in HbA1c, fasting plasma glucose (FPG), seven-point self-monitored plasma glucose (SMPG) profiles, hypoglycemic events, treatment-emergent adverse events (TEAEs), and anti-insulin antibodies (AIAs). RESULTS: Five hundred seven patients were randomized (SAR-Lis n = 253; Ly-Lis n = 254). Least square (LS) mean (SEM) change in glycosylated hemoglobin (HbA1c) (baseline to week 26; primary endpoint) was similar in both treatment groups (SAR-Lis: -0.42% [0.051]; Ly-Lis: -0.47% [0.050]). Noninferiority at prespecified 0.3% noninferiority margin and inverse noninferiority were demonstrated (LS mean difference of SAR-Lis vs. Ly-Lis: 0.06% [95% confidence interval: -0.084 to 0.197]). At week 52 (end of extension period) versus week 26, a small HbA1c increase was observed in both groups. FPG and seven-point SMPG profile changes, including postprandial glucose excursions, were similar between groups. At week 52, similar changes in mean daily mealtime and basal insulin doses were observed. Hypoglycemia, TEAEs, and AIAs (incidence, prevalence) did not differ between groups. CONCLUSIONS: Results from this controlled study in patients with T1DM also using GLA-100 support similar efficacy and long-term safety (including immunogenicity) of SAR-Lis and Ly-Lis.