Biosimilar Insulin Exhibits Interchangeability with Reference Product in Type 1 Diabetes


Pharmacokinetic exposure of the biosimilar insulin and reference product showed similarity, supporting the interchangeability between the two insulin aspart products.

Viral N. Shah, MD | Image Credit: University of Colorado

Viral N. Shah, MD

Credit: University of Colorado

Alternating use of biosimilar insulin apart (SAR-Asp) and the insulin aspart reference product (Novolog [NN-Asp]) led to equivalent pharmacokinetic exposure among ≥200 adults with type 1 diabetes (T1D), according to new research.1

Results from the randomized, open-label, phase 3 GEMELLI X trial revealed alternating doses of the biosimilar showed similar PK exposure, including the area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax), to continuous use of the reference product at 16 weeks of study.

“Taken together with the clinical data, the results confirm that alternating administration of SAR-Asp and NN-Asp does not lead to different clinical results when compared with continuous use of NN-Asp, supporting interchangeability between these two insulin products,” wrote the investigative team, led by Viral N. Shah, MD, Barbara Davis Center for Diabetes, the University of Colorado Anschutz Medical Campus.

The switching trial was designed according to 2017 draft guidance from the US Food and Drug Administration (FDA) on the interchangeability of a biosimilar with the originator drug.2 Development of SAR-Asp was initiated on this draft guidance as an interchangeable biosimilar to the reference product NovoLog (NN-AsP). Interchangeability designations allow a biosimilar substitute for the reference product by a pharmacist without needing approval from the prescriber and could result in significant cost savings.

Trials supporting interchangeability are designed to evaluate if clinical performance is affected by multiple switches between the reference product and the biosimilar, particularly in the pharmacokinetics or immunogenicity profiles. The GEMELLI X trial randomized 210 adults with T1D treated with once-daily insulin glargine U100 as basal insulin to four 4-week periods of alternating treatment with SAR-Asp and NN-Asp (switching group) compared with 16 weeks of continuous NN-Asp (non-switching group).1

After completion of the 16-week treatment period, study participants attended the study site in the morning, fasted, and went without injecting their study insulin for ≥8 hours. Participants underwent blood sampling for predose plasma concentration of insulin aspart and then received a single subcutaneous injection of 0.15 U/kg SAR-Asp in the switching group (n = 95) or NN-ASP in the non-switching group (n = 105).

For the analysis, the co-primary PK endpoints of the study were the area under the plasma insulin concentration-time curve (AUClast), AUC versus time curve extrapolated to infinity (AUCinf), and the maximum observed insulin aspart concentration (Cmax) following injection of a single dose of 0.15 U/kg SAR-Asp or NN-Asp at week 16.

Upon analysis, the study showed that AUClast and AUCinf were generally alike between the treatment groups, while the geometric mean Cmax was also similar between groups. The point estimates for the treatment ratio of all 3 primary PK endpoints were close to 1.0, according to the data.

Moreover, the 90% confidence intervals (CIs) of the treatment ratios for AUClast and AUCinf were within 0.8 to 1.25. For Cmax in the primary analysis, the upper 90% confidence limit of the treatment ratio was 1.32, owing to the profiles of 3 individuals with extremely high Cmax values.

Results from a prespecified sensitivity analysis excluding the confounding impact of highly implausible PK profiles showed the average AUClast, AUCinf, and Cmax were similar between treatment groups. The 90% Cis of treatment ratios for all 3 PK parameters were within the 0.80 to 1.25 interval, with post estimates close to 1.0.

More recent guidelines from the FDA do not require dedicated switching PK assessment studies, with multiple interchangeable insulin products having been approved without these studies.3 As both the disease cost of diabetes and the number of diagnosed patients continue to increase, the price of insulin will continue to be a point of concern for many patients.1

“The introduction of biosimilar insulin products may help to further reduce drug treatment costs as they are priced lower than the originator products, while conferring comparable efficacy and safety, thereby facilitating greater access to insulin treatment,” they wrote.


  1. Shah VN, Al-Karadsheh A, Barnes C, et al. 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. Diabetes Obes Metab. Published online October 25, 2023. doi:10.1111/dom.15341
  2. US Food and Drug Administration Center for Drug Evaluation and Research (CDER). Draft guidance for industry. Considerations in demonstrating interchangeability with a reference product. 2017:1–30
  3. US Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for industry. Considerations in demonstrating interchangeability with a reference product. 2019:1–20
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