Similar PK Observed Between High-Concentration, Reference Adalimumab-adbm

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The citrate-free, high-concentration formulation and reference formulation of the biosimilar adalimumab-adbm (Cyltezo) demonstrated comparable pharmacokinetic (PK) and immunogenicity profiles among a cohort of healthy participants, according to a study published in Expert Opinion on Biological Therapy.¹ Both concentrations were shown to be safe and well-tolerated.

Adalimumab-adbm, a recombinant IgG1 human monoclonal antibody tumor necrosis factor blocker, was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of immune-mediated inflammatory diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis, and uveitis. In October 2021, it became the first interchangeable biosimilar to adalimumab.²

In the 14-week, double-blind, randomized, single-dose, parallel-arm phase 1 VOLTAIRE-HCLF trial, investigators enrolled a cohort of healthy, adult volunteers to compare the bioavailability of citrate-free, high-concentration and reference formulations of adalimumab-adbm. They also assessed the immunogenicity, tolerability, and safety of the formulations.

“Notably, larger subcutaneous injection volumes are typically associated with increased patient discomfort and pain at the injection site, both of which may contribute to poor patient outcomes and medication adherence,” wrote a team of investigators from Boehringer Ingelheim. “While conflicting evidence exists regarding the impact of faster injection speed on injection site pain, the combined effect of faster injections with lower drug volume has the advantage of increased tolerability and quickening the injection process for patient self-administration.”

The primary endpoints of the trial were to assess the bioavailability between formulations using the area under the concentration–time curve of the analyte in plasma from 0 to 1344 hours after dose administration (AUC_0–1344), AUC of the analyte in plasma from dosing extrapolated to infinity (AUC_0–∞), and the maximum measured concentration of the analyte in plasma (C_max).

Immunogenicity was assessed using plasma samples collected at baseline, day 15, day 29, and day 57 to determine the occurrence and titer of anti-drug antibodies (ADAs) and neutralizing antibodies (nAbs). Safety was evaluated using physical examinations and laboratory testing, and all adverse events (AEs) were recorded, including treatment-emergent AEs (TEAEs) and serious AEs (SAEs).

A total of 200 subjects with a body mass index of 18.5–29.9 kg/m² who did not have previous exposure to adalimumab were randomized 1:1 to receive a single subcutaneous injection of either the high-concentration formulation (40 mg/.4 mL) or reference formulation (40 mg/.8 mL). Patients received 13 follow-up visits between day 3 and day 57, followed by a safety follow-up period of up to 70 days.

For all primary PK endpoints, the geometric mean ratios and 90% confidence intervals (CIs) of AUC_0–1344, AUC_0–∞, and C_max for both formulations were well within the bioequivalence acceptance range (80-125%) at 101.88% (93.31–111.23%), 105.38% (95.06–116.81%), and 91.29% (84.38–98.76%), respectively.

At baseline, a total of 19 subjects (19.2%) in the high-concentration cohort and 11 (10.9%) in the reference cohort were ADA-positive, with a median titer of 4 (range: 1-32) and 8 (range: 1-128), respectively. No differences were observed in the proportion of ADA-positive subjects or ADA titers across treatment arms during the study period.

Compared with the reference formulation group, patients in the high-concentration formulation cohort reported a lower incidence of AEs (18.2% vs 26.0%, respectively) and local reactions (1 event vs 16 events, respectively). The most common TEAE was headache (5.0% of patients) and most AEs were categorized as mild. No SAEs were reported across treatment arms.

Investigators mentioned limitations such as the small sample size and the inclusion of only healthy participants between a certain age range (18-55 years). In addition to providing an imperfect assessment of immunogenicity, tolerability, and safety, these restrictions also exclude both pediatric and elderly patients, with and without comorbidities. However, they noted other phase 3 studies evaluating adalimumab-adbm reported similar PK, immunogenicity, efficacy, and safety to the reference drug across several disease indications.

“Based on these results, no clinically relevant differences in efficacy or safety between the high-concentration and reference adalimumab-adbm formulations would be expected in a clinical setting,” investigators concluded.

References

1. ^{Moschetti V, Buschke S, Bertulis J, Hohl K, McCabe D. Relative bioavailability, immunogenicity, and safety of two adalimumab-adbm formulations in healthy volunteers: a double-blind, randomized, single-dose, parallel-arm Phase I trial (VOLTAIRE-HCLF). Expert Opin Biol Ther. Published online May 19, 2024. doi:10.1080/14712598.2024.2354902}
2. ^{U.S. FDA. FDA approves cyltezo, the first interchangeable biosimilar to humira 2021. [cited 2023 Sep 19]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-cyltezo-first-interchangeable-biosimilar-humira}