Insulin-R (Biocon), a proposed biosimilar referencing Eli Lilly’s Humulin-R, a short-acting recombinant human insulin, demonstrated equivalence in a pharmacokinetic (PK) and pharmacodynamic (PD) study published in Diabetes, Obesity and Metabolism.

Insulin costs have increased dramatically in recent years, and the authors of the study pointed out that high costs for many patients result in “nonadherence or rationing of insulin, leading to diabetic complications with early and increased morbidity and mortality.” The availability of biosimilars could help improve access to insulin, and the authors noted, “the Endocrine Society has made strong recommendations to expedite the approval of insulin biosimilars as one of the policies to increase access to life-saving insulins.”

According to the investigators, the proposed biosimilar has demonstrated similarity in structure and function in physicochemical analyses and nonclinical studies, and the current study evaluated PK/PD parameters in healthy subjects. They carried out a crossover study in which 42 healthy male participants aged 18 to 55 were randomized to a sequence of single doses of the reference product and the biosimilar. After a fast of at least 10 hours, the study drugs were administered, and plasma insulin and glucose infusion rates were assessed over 12 hours.

The authors noted that the FDA and European Medicines Agency (EMA) recommend the use of the euglycemic glucose clamp technique for evaluating PK/PD parameters of biosimilar insulin products. The clamp device automatically adjusted the glucose infusion rate (GIR) to maintain each subject’s blood glucose concentration at a target level of 81 mg/dl “with minimum deviations” over the 12 hours after injection of the study drugs.

The primary PK endpoints were area under the insulin concentration-time curve (AUC ins) and maximum insulin concentration (Cmax). The 90% confidence intervals (CIs) for both were within the predefined eqiuvalence margins of 80% to 125%. The confidence intervals were 97.02-101.81 for AUC ins and 87.34-97.61 for Cmax.

For PD, primary endpoints were area under the glucose infusion rate curve (AUC GIR) and maximum glucose infusion rate (GIRmax). The authors said GIR is “a surrogate PD marker” for insulins that “correlates with clinical efficacy.” Equivalence in PD parameters was also demonstrated, with 90% CIs within the predefined margins. The 90% CIs were 92.63-104.79 for AUC GIR and 89.46-101.74 for GIRmax. The investigators noted that, “although secondary end points were not expected to meet bioequivalence criteria,” some of the secondary PK end points (AUC ins 0-2 hours, AUC ins 0-6 hours, and AUC ins 0-infinity) and all the secondary PD end points also met the equivalence criteria.

No serious adverse events were reported in the study, and there were no significant differences in the safety profile between the originator and proposed biosimilar, according to the investigators. A total of 39 treatment-emergent adverse events (TEAE) were reported. Twelve participants treated with the biosimilar and 14 participants treated with the reference product reported adverse events. Most TEAEs were mild, and the most common were headache and injection-site reactions. Furthermore, the authors wrote, “there were no clinically significant findings in hematology, biochemistry or urinalysis laboratory tests that were assessed throughout the study.”

The investigators concluded their study demonstrated PK/PD equivalence between Insulin-R and the reference product Humulin R, and that both drugs were well-tolerated. Recombinant human insulin, they said, “is the standard of care in the management of diabetes,” and they proposed “introduction of Biocon’s Insulin-R can ensure reliable and affordable access, potentially bringing better management of diabetes and its complications and reducing the subsequent financial burden in the US and globally.”