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Patients receiving tocilizumab and LZM008 showed comparable pharmacokinetic properties after a single intravenous dose.
The pharmacokinetic characteristics, immunogenicity, and safety profiles were comparable between a recombinant humanized anti-human interleukin (IL)-6R monoclonal antibody LZM008 injection and the reference originator tocilizumab, according to a study published in Frontiers in Pharmacology.1
Biosimilars, unlike generic products, are highly similar to the reference products and highly dependent on manufacturing steps. Investigators noted that the same protein created by different methods or in different facilities may have a different safety, efficacy, and purity profile. Therefore, the process of creating these drugs can be a challenging ordeal and evaluation via clinical trials is critical.2
“Pharmacodynamic studies at molecular and cellular levels have been carried out in the preclinical study, and studies on pharmacokinetics, pharmacodynamics, and immunogenicity have also been carried out in cynomolgus monkeys (unpublished data),” wrote a team of Chinese investigators. “The results of preclinical studies have demonstrated high similarities between LZM008 and tocilizumab (unpublished data). Until now, there is no biosimilar for tocilizumab marketed in China, and LZM008 might be an alternative, with the advantage of lower price and higher accessibility.”
The randomized, double-blinded, paralleled, 2-center, phase 1 trial, 96 adult Chinese males, aged 18 to 45 years, were randomized to receive either 4 mg/kg intravenous LZM008 or tocilizumab and were then assessed for a period of 28 days. Pharmacokinetic bioequivalence, the primary endpoint, was determined using the maximum serum concentration, the area under the serum concentration-time curve (AUC from 0 to the last detectable drug concentration [AUC0-t]) and AUC0-∞. Blood samples to determine pharmacokinetics were collected pre-dose and at a variety of time points after infusion and immunogenicity samples were collected at screening day and then again at day 14 and day 28 after infusion.
Safety was evaluated using laboratory tests, vital signs, physical examinations, and electrocardiograms. A bridged electrochemiluminescence immunoassay measured anti-drug antibodies (ADAs). ADA-positive samples were additionally evaluated for the presence of neutralizing antibodies (NAbs). Adverse events were analyzed based on the type, timing, seriousness, and relatedness of the events.
Among those receiving tocilizumab (n = 47) and LZM008 (n = 49), patients showed comparable pharmacokinetic properties. After a single intravenous infusion, the Cmax and AUC0-∞ values of LZM008 reached 87.99 μg/mL and 11,526.70 h μg/mL, respectively. These patients also achieved a Tmax 1.98 h and the half-life (t1/2) was 83.45 h. The 90% confidence intervals (CIs) for for Cmax, AUC0-t, and AUC0-∞ were all within the 80% and 125% range.
Positive ADA test results occurred in 2% (n = 1) of patients in the LZM008 group and 6.4% (n = 3) patient in the tocilizumab group. Treatment emergent adverse events (TEAEs) were similar among patients in the biologic and biosimilar groups (100% vs 98%, respectively) and the incidence of TEAEs of grade III or worse were similar (12.8% vs 8.2% respectively). The most common TEAEs were the decrease in blood fibrinogen and neutrophil counts. All reported TEAEs of grade IV were reverted to baseline after day 36.
Investigators note that not including female subjects may have limited the results. Although the study demonstrated the pharmacokinetic consistency between the drugs, the efficacy should be verified in larger studies in the future.
“LZM008 can further be developed as a potential tocilizumab biosimilar in RA patients,” investigators concluded.