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

Abstract

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) (SAR_Asp-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 SAR_Asp-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 SAR_Asp-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 SAR_Asp-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 SAR_Asp-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.

Keywords: Biosimilar insulin; GEMELLI M; Insulin aspart mix; Premix; SAR341402; Subgroup by prior premix insulin.

Fig. 1

Least squares mean change in HbA1c (%) from baseline to week 26 in total study population and by subgroup of prior of prior premix insulin (NovoMix 30 or Humalog Mix 25/Liprolog Mix 25) using ANCOVA analysis (with return to baseline multiple imputation) (ITT population). The statistical model used for the analysis is described in Table S2. P value for treatment-by-subgroup interaction = 0.4594 at week 26. ANCOVA analysis of covariance

Fig. 2

Daily premix insulin doses (U/kg) in participants at baseline, day 1, and week 26 for total study population and by subgroup of prior premix insulin (NovoMix 30 or Humalog Mix 25/Liprolog Mix 25) (safety population). Data are mean ± standard error. Insulin doses are rounded to two 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, 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-Mix versus NN-Mix for participants with one or more hypoglycemic events during the 26-week on-treatment period by subgroup of prior premix insulin (NovoMix 30 or Humalog Mix 25/Liprolog Mix 25) (safety population). Results are based on logistic regression model with fixed-effect terms for treatment group, randomization strata of geographical region (Indian, non-Indian), type of diabetes (T1D, T2D), and screening HbA1c (less than 8%, 8% or higher), subgroup, and subgroup-by-treatment interaction. For the category of severe hypoglycemia, randomization strata were removed from the model because of nonconvergence. ^aP values of subgroup-by-treatment interaction based on the model described above. n number of participants with one or more treatment-emergent events, % percentage of participants with one or more event, NC model did not converge

Fig. 4

Anti-insulin aspart antibody (AIA) and neutralizing antibody (NAb) response at baseline and week 26 by subgroup of prior premix insulin (NovoMix 30 or Humalog Mix 25/Liprolog Mix 25) (AIA population). Data shown as percentage of participants with each outcome [see ESM Table S5 (AIA) and ESM Table S6 (NAb) for the denominators]. ^aPrevalence: participants with at least one positive AIA/NAb sample at baseline or postbaseline. ^bIncidence: participants with newly positive AIA/NAb postbaseline (treatment-induced) or with ≥ 4-fold increase in titer (treatment-boosted) (i.e., participants with treatment-emergent AIAs/NAbs). AIA anti-insulin aspart antibody, NAb neutralizing antibody