Biosimilar Liraglutide Noninferior to Reference Product in Persons with Type 2 Diabetes: Phase 3 Trial

The biosimilar liraglutide (Meltitide^®) was found noninferior in efficacy to the branded reference product (Victoza^®) in a phase 3 clinical noninferiority trial and demonstrated a comparable safety profile, according to findings published online in Diabetes Therapeutics.¹

The biosimilar and the reference product, a glucagon-like peptide-1 (GLP-1) receptor agonist, were matched in lowering hemoglobin A1c (HbA1c) over the 26-week study and had similar salutary effects on body weight, lipids, and blood pressure.¹

Liraglutide was approved by the US Food and Drug Administration (FDA) in January 2010 as an adjunct to diet and exercise to reduce hyperglycemia in individuals with type 2 diabetes (T2D). GLP-1 mimetics, as a class, are recommended by clinical guidelines as initial treatment for persons diagnosed with T2D who have or are at elevated risk for cardiovascular disease (CVD).²

Findings from preclinical studies of biosimilar liraglutide found “no meaningful differences” from the reference liraglutide, authors wrote. The research team, led by Dr Mohammad Ebrahim Khamseh, director of the Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, points to the lower cost of biosimilar agents compared with the products they mimic. They suggest that given the rapidly escalating incidence of diabetes worldwide, effective, and affordable medications are needed to expand access to therapy and to reduce the cost burden on the health care system at large.¹

The current phase 3 clinical trial was designed to assess the noninferiority of biosimilar liraglutide for reduction of HbA1c and other efficacy measures and to compare its safety profile with reference liraglutide. The randomized, double-blind, active-controlled, parallel-group, noninferiority study was conducted from July 2019 to December 2021 across 17 study centers in Iran.¹

Khamesh and colleagues recruited adults aged between 18 and 80 years with inadequately controlled T2D and HbA1c levels 7–10.5% on 2 or more oral glucose-lowering medications with stable doses for 3 months or longer; baseline body mass index range was 20-45 kg/m². Eligible participants were randomly assigned in a 1:1 ratio to receive daily 1.8 mg biosimilar liraglutide or liraglutide for 26 weeks. The primary outcome of interest was noninferiority of the biosimilar to the reference liraglutide with a prespecified margin of 0.4%.

The secondary outcomes were proportion of participants who reached HbA1c targets (HbA1c <7%; HbA1c ≤6.5%) and additional measures of efficacy comprised of changes in body weight, fasting plasma glucose, blood pressure, pulse rate, lipid profile, and estimated glomerular filtration rate from baseline to week 26. Researchers also assessed immunogenicity and adverse outcomes between the 2 groups.

FINDINGS¹

The final cohort numbered 300, with 150 individuals assigned to each study arm. A total of 235 patients were included in the per-protocol (PP) group, 112 receiving biosimilar liraglutide and 123 receiving liraglutide.

Khamesh et al reported a decrease in HbA1c levels in both groups over the first 12 weeks of the study and that values remained stable through week 26.

The mean changes in HbA1c from baseline to week 26 were similar between groups, –1.76% in the biosimilar liraglutide group and –1.59% in the liraglutide group (difference, –0.18; 95% CI, –0.50 to 0.15; P = .288). The team also reported that the upper limit of the one-sided 95% CI for the mean difference between the 2 study arms was lower than the predefined noninferiority margin (0.4%), confirming noninferiority of the biosimilar to the reference product in lowering HbA1c. Findings were consistent between the PP and intention-to-treat populations, according to the study.

Secondary outcomes were analyzed among 112 patients in the biosimilar liraglutide and 125 patients in the reference liraglutide groups. Investigators identified no statistically significant differences between the 2 study arms in the proportion of patients achieving HbA1c <7% (P = .210), the range of other efficacy parameters (P > .05), or reported adverse events (P = .916).

Overall, 126 (83.44%) patients in the biosimilar liraglutide group and 125 (83.89%) patients in the liraglutide group experienced ≥1 adverse event, with gastrointestinal disorders most frequent and most considered mild or moderate. The observed safety profiles matched those reported in other studies investigating liraglutide. Analysis of serum samples from both groups found no evidence of anti-liraglutide antibodies.

The primary study limitations were the short duration and small sample size, the investigators noted, suggesting that a longer study with a larger sample “might have enabled us to detect differences between the two medications in terms of rare adverse events.”

References

1. Esteghamati A, Zamanzadeh M, Malek M, et al. Efficacy and safety of a biosimilar liraglutide (Melitide) versus the reference liraglutide (Victoza) in people with type 2 diabetes mellitus: a randomized, double-blind, noninferiority clinical trial. Diabetes Ther. Published online September 14, 2023. doi:10.1007/s13300-023-01462-w

2. American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2023. Diabetes Care. 2021;44(Suppl_1):S111–24. doi:10.2337/dc23-S009