Phase 1 Study Demonstrates Bioequivalence Between Enoxaparin Biosimilar vs Reference Product

A pharmacodynamic study of enoxaparin sodium biosimilar Cloti-Xa found anti-factor Xa and anti-factor IIa activity within predefined bioequivalence margins in healthy participants, supporting biosimilarity.

Enoxaparin sodium, a low-molecular weight heparin (LMWH), is an antithrombotic medication used to treat or prevent arterial and venous thromboembolism, such as in deep vein thrombosis, pulmonary embolism, and acute coronary syndrome. Producing LMWH biosimilars “is a challenging task,” according to the authors: because of structural variability between molecules, different LMWHs tend to differ in their pharmacokinetic (PK) and pharmacodynamic (PD) properties.

The study compared a single dose of the biosimilar (Cloti-Xa; Venus Remedies Limited, India) to the originator (Clexane, Lovenox) in healthy volunteers in a randomized, double-blind, crossover study. Under fasting conditions, 24 male participants (mean age 35) were randomly administered subcutaneous injections of the biosimilar and reference product, separated by a 1-week washout period. Blood samples were taken multiple times over 24 hours after administration of the study drugs.

According to the investigators, pharmacokinetics of LMWHs cannot be assessed with conventional methods. As such, PK properties and bioavailability of LMWHs are typically determined using pharmacodynamic (PD) surrogates such as anti-Xa activity, anti-IIa activity, and activated partial thromboplastin time (aPTT). In line with European Medicines Agency (EMA) recommendations, the authors measured anti-Xa and anti-IIa as the primary PD endpoints to compare the biosimilar to the reference LMWH. Secondary parameters included the ratio of anti-Xa/anti-IIa activity, tissue factor pathway inhibitor (TFPI) activity, and aPTT.

Pharmacodynamic Parameters Met Criteria for Bioequivalence

The 90% confidence intervals (CIs) of the ratio of the primary PD parameters of the biosimilar to reference product were all within the predefined bioequivalence margins of 80% to 125%. For anti–Xa activity, the 90% CI for maximum activity (Amax) was 105.50% to 113.90%, and for area under the effect curve from 0 to the last measured activity (AUECt), the 90% CI was 103.97% to 112.08%. For anti-IIa activity, the 90% CI for Amax was 106.56% to 117.90% and the 90% CI for AUECt was 107.35% to 124.86%.

The authors noted that enoxaparin has a large ratio of anti-Xa to anti-IIa, and its anticoagulant effect correlates directly with its anti-Xa activity. They found that the CIs for the ratios of anti-Xa to anti-IIa activity were also within the bioequivalence margins, 95.05%-100.62% for Amax and 86.21%-100.75% for AUECt.

Secondary PD endpoints “compared well” between the 2 products, the authors said. Also, they submitted data on TFPI activity and aPTT as supportive evidence for biosimilarity, which they said were similar between the 2 products. All of the 90% CIs for TFPI and aPTT were within the bioequivalence margins except for AUECt for aPTT, which crossed the upper limit (95% CI, 98.80-129.14).

Cloti-Xa Was Well-tolerated By Healthy Subjects

Both the biosimilar and reference product were “well-tolerated” by the study subjects. Two adverse events (AEs) were reported, both of which were mild. One was a decrease in platelet count, possibly related to the study drug (Cloti-Xa). The other AE occurred in the originator group, but was considered unlikely to be related to the study drug. There were no serious AEs.

The authors concluded that Cloti-Xa showed bioequivalence to the reference product after a single dose in healthy volunteers. They wrote that dose they used “has been found effective irrespective of the human body weight,” and was sufficient to demonstrate bioequivalence. However, they recommended higher doses be used in future bioequivalence studies, as previous clinical trials on other enoxaparin compounds have been conducted using multiple doses.

Reference

Saxena S, Chaudhary M, Chaudhary S, Aggarwal A. Bioequivalence of a biosimilar enoxaparin (Cloti-Xa™) and its innovator (Clexane® ): A single-dose, randomized, double-blind, two-period, two-treatment, two-sequence, crossover, balanced study in healthy human subjects. Pharmacol Res Perspect. 2022;10(4):e00979. doi:10.1002/prp2.979