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

Abstract

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.

Keywords: Biosimilar insulin; GEMELLI 1; Insulin aspart; SAR341402; Subgroup by prior mealtime insulin.

Figures

Fig. 1

Least squares (LS) mean change in hemoglobin A1c (HbA1c) (%-points) from baseline to week 26 (a) and week 52 (b) in the total study population and by subgroup of prior mealtime insulin (NovoLog/NovoRapid or Humalog/Liprolog) using the analysis of covariance model (with retrieved dropout multiple imputation) (intent-to-treat population). The statistical model used for the analysis is described in ESM Table S2. P value for treatment by subgroup interaction = 0.3566 at week 26 and 0.5677 at week 52. CI Confidence interval, NN-Asp NovoLog®/NovoRapid® insulin aspart, SAR-Asp biosimilar SAR341402 insulin aspart, SD standard deviation, SE standard error

Fig. 2

Daily mealtime insulin doses (U/kg) in participants at baseline, day 1, week 26, and week 52 for the total study population and by subgroup of prior mealtime insulin (NovoLog/NovoRapid or Humalog/Liprolog) (safety population). Data are presented as the mean ± SE. Insulin doses are rounded to 2 decimal places. Baseline insulin dose is defined as the median of daily doses available in the week prior to the first injection of study medication (doses of prestudy insulin). The value at day 1 is defined as the median of daily doses available in the week after the first injection of study medication. For week 26 (week 52), the value presented is the median of daily doses available in the week prior to the visit

Fig. 3

Forest plot of the odds ratio of SAR-Asp vs. NN-Asp for participants with ≥ 1 hypoglycemic event during the 6-month (a) and 12-month (b) on-treatment period by subgroup of prior mealtime insulin (NovoLog/NovoRapid or Humalog/Liprolog) (safety population). Results are based on logistic regression model with fixed-effect terms for treatment, the randomization strata of geographical region, and type of diabetes (Europe type 1 diabetes [T1D], USA T1D, USA type 2 diabetes, Japan T1D), screening HbA1c (< 8.0, ≥ 8.0%), subgroup, and subgroup-by-treatment interaction. For the category of any hypoglycemia, randomization strata were removed from the model due to non-convergence. aP values of subgroup-by-treatment interaction are based on the model described above. The number of participants with ≥ 1 treatment-emergent event, number of participants included in the analysis population, and percentage of participants with ≥ 1 event are shown in ESM Table S4

Fig. 4

Anti-insulin aspart antibody (AIA) response at baseline (a), week 26 (b), and week 52 (c) by subgroup of prior mealtime insulin (Novolog/NovoRapid or Humalog/Liprolog) (AIA population). Data are shown as the percentage of participants with each outcome (see ESM Table S6 for the denominators). aN = 107 in 52-week analysis. bPrevalence: participants with at least 1 positive AIA sample at baseline or post-baseline. cIncidence: participants with newly positive AIA post-baseline (treatment induced) or with ≥ fourfold increase in titer (treatment boosted) (i.e., participants with treatment-emergent AIAs).