An Open Label, Non Randomized, Propspective Phase IV Clinical Trial Evaluating the Immunogenicity of Branded Enoxaparin Versus Biosimilars In Healthy Volunteers.

Abstract 1086

Biosimilar enoxaparin preparations are in use outside the U.S. Due to compositional variations, their interaction with platelet factor 4 (PF4) differs leading to differential immunogenic responses between branded and biosimilar agents. To compare their immunogenic response, branded enoxaparin (Clexane®, Sanofi-Aventis) and a biosimilar version (Cutenox®, Gland-Pharma) were administered to healthy volunteers (n=110/drug) at a dose of 40 mg SQ for10 days. Blood samples drawn on days 1 and 10 were analyzed for anti-heparin/PF4 antibody (A-HPF4-Ab) titers and subtypes by ELISA (GTI, Brookfield, WI). Treatment with each LMWH resulted in comparable A-HPF4-Ab generation as compared by using the total absorbance for each population (p<0.05). However in the thrombin generation assays clexane group showed a stronger inhibition (45+12% vs 32+9%). None of these antibodies activated platelets as determined by the serotonin release assay. The two groups alos showed comparable AXa and AIIa responses (p<0.05). Antibody subtyping demonstrated different profiles between LMWHs. For IgG (Clexane1=0.15±0.04, Clexane10=0.21±0.06, Cutenox1=0.17±0.04, Cutenox10=0.28±0.10) with a significant time effect (p<0.0001), a significant drug effect (p<0.0001), and a significant time by drug interaction (p=.0009). Post hoc comparisons showed a difference between the drugs at time 0 (p=0.03), a difference between the drugs at time 10 (p<0.0001) and a significant time effect for each drug (p<0.0001). For IgA (Clexane1=0.12±0.02, Clexane10=0.15±0.02, Cutenox1=0.12±0.03, Cutenox10=0.13±0.02) with significant effects for time (p<0.0001), drug (p=0.0078) and for the drug × time interaction (p<0.0001). The post hoc comparisons showed a significant drug effect at time 10 (p<0.0001). There was a significant time effect for Clexane (P<0.0001) but not for Cutenox. For IgM (Clexane1=0.11±0.01, Clexane10=0.13±0.02, Cutenox1=0.11±0.03, Cutenox10=0.13±0.02), there was only a time effect (p<0.0001). The post hoc comparisons showed no difference between drugs at either time, but significant time effects for each drug (p<0.0001). The immunogenic potential of LMWHs varies in terms of ability to generate A-HPF4-Ab, the antibody subtypes generated, and their cross-reactivity with pre-formed A-HPF4-Ab. Such parameters may be useful in defining the bioequivalence of generic LMWHs. Future studies evaluating the immunogenicity of different compounds in patients exposed to biosimilar drugs are warranted.