A Randomized Pharmacokinetic Study in Healthy Male Subjects Comparing a High-concentration, Citrate-free SB5 Formulation (40 mg/0.4 ml) and Prior SB5 (Adalimumab Biosimilar)

Study Population

The study population comprised healthy male subjects. Key inclusion criteria were age of 18–55 years, body weight of 65.0–90.0 kg, and a body mass index (BMI) of 20.0–29.9 kg/m2 at screening and baseline (day 1). In addition, eligible subjects were to show no clinically relevant abnormalities in 12-lead electrocardiogram (ECG), vital signs, physical examination, and clinical laboratory tests at screening and baseline. Key exclusion criteria were a diagnosis of active or latent tuberculosis, previous treatment with ADL, and known or suspected clinically relevant drug hypersensitivity to ADL or to any of the excipients.

Study Design

This was a randomized, single-blind, two-arm, parallel-group, single-dose study performed at Parexel Early Phase Clinical Unit, Berlin, Germany, between August 2020 and May 2021 (clinicaltrials.gov identifier NCT04514796). The final study protocol was approved by the local Independent Ethics Committee (IEC; Ethics committee of the state of Berlin, State Office of Health and Social Affairs, Berlin, Germany, reference number 20/0178). This study was conducted in accordance with the Declaration of Helsinki (1996) and is consistent with the International Council for Harmonization Good Clinical Practice guidelines and applicable local regulatory requirements and laws. Written informed consent was obtained from each subject before enrolment. The consent form was reviewed and approved by the IEC prior to use.

Eligible subjects were randomized in a 1:1 ratio to receive a single 40-mg dose of either SB5-HC or SB5-LC, subcutaneously injected with a pre-filled syringe in the left or right upper abdominal quadrant of the periumbilical area on day 1. Subjects were observed for 57 days during which PK, safety, tolerability, and immunogenicity measurements were performed. Primary endpoints were the area under the concentration–time curve from time zero to infinity (AUCinf) and maximum serum concentration (Cmax). Secondary PK endpoints included area under the concentration–time curve from time zero to the last quantifiable concentration (AUClast), time to Cmax (Tmax), apparent volume of distribution during the terminal phase (Vz/F), terminal rate constant (λz), terminal half-life (t1/2), apparent total body clearance (CL/F), and percentage of AUCinf due to extrapolation from time of last measurable concentration (Tlast) to infinity (%AUCextrap). The safety endpoints were adverse events (AEs) and serious AEs (SAEs), clinical laboratory values, 12-lead ECG, vital signs, physical examination, and injection site assessment. Immunogenicity endpoints were the incidence of ADAs and neutralizing antibodies (NAbs) to ADL.

Pharmacokinetic Evaluation

Blood samples for PK analysis were collected at 0 (pre-dose), 24, 48, 96, 120, 144, 168, 216, 264, 336, 408, 504, 600, 696, 840, 1008, and 1344 hours (h) post-dose. Subjects were discharged on day 2 with the rest of study period consisting of outpatient visits. Serum concentrations of ADL were measured using a validated enzyme-linked immunosorbent assay (ELISA) specific for the detection and quantification of ADL. The lower limit of quantitation was 0.05 μg/ml, and the upper limit of quantitation was 1.50 μg/ml. Intra- and inter-assay precision and accuracy displayed a percent coefficient of variation (CV%) of 6.6% and 14.8%, respectively. The primary endpoint AUCinf was calculated as AUClast plus last observed concentration (Ct) divided by λz. Linear regression after log-transformation using the last three (or more) non-zero concentrations was used to calculate λz. Terminal half-life (t1/2) was calculated by ln(2)/λz.

Safety Evaluation

All reported terms for AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA®) version 23.0. Specifically, injection sites were assessed for redness, bruising, swelling, itching, and pain using a numeric rating scale from 0 to 3 (0 = none, 1 = mild, 2 = moderate, 3 = severe). The total score was the sum of these points, ranging from 0 to 15. If an injection site reaction reached a total score sum ≥ 2, it was recorded as an AE. The injection site assessment was conducted at six time points (pre-dose, immediately post-dose, 15 minutes (min) post-dose, 24 h, 48 h, and 96 h post-dose). For the pain evaluation during injection site assessment, a visual analogue scale (VAS; 0 mm = no pain; 100 mm = intolerable pain) was used and the readouts were categorized as no pain (scale < 10 mm), mild pain (scale ≥ 10 to < 50 mm), moderate pain (scale ≥ 50 to < 70 mm), and severe pain (scale ≥ 70 mm) with pain defined to interfere with life if VAS was ≥ 50 mm [9,10,11].

Immunogenicity Evaluation

Blood samples for immunogenicity were collected on day 1 (pre-dose), day 26, and day 57 to detect ADAs and NAbs to ADL. The samples for immunogenicity were analyzed using the Meso Scale Discovery® platform (Rockville, MD, USA) with acid dissociation to release any ADAs complexed with free drug.

Statistical Methods

The original sample size of 232 subjects to achieve 90% power at a 5% dropout rate was reduced to 188 subjects to achieve 85% power at a 1% dropout rate. This change was implemented as a protocol amendment during the COVID-19 pandemic in accordance with local conditions. A sample size of 93 completing subjects per treatment group provided 85% power to detect a 20% difference in PK between the test and reference investigational product based on the assumption of 5% difference in true geometric means between test and reference group and inter-subject percent coefficient of variation (CV%) of 46%. Considering AUCinf and Cmax as the primary endpoints for this clinical study, 41% inter-subject CV% was used as a conservative approach, based on known variability of PK parameters in previous studies involving SB5-LC [5, 6]. An additional 5% uncertainty was added to account for the different concentration of the new formulation SB5-HC. Sample size was calculated in respect to two one-sided t tests, each at 5% significance level.

The safety set consisted of all subjects who received the study drug, and the PK analysis set consisted of all subjects who were included in the safety set and had at least one PK sample analyzed without any major protocol deviation that has an impact on PK analysis.

Statistical analyses of primary endpoints were based on an analysis of variance (ANOVA) model with treatment as fixed effect. The difference in geometric least squares means (LSMeans) of primary endpoints between the SB5-HC and SB5-LC group and the associated 90% confidence intervals (CIs) for the ratio of the geometric LSMeans were determined. Back transformation provided the ratio of geometric LSMeans and 90% CIs for these ratios. Equivalence of the primary endpoints was determined if the 90% CI for the ratio of geometric LSMeans of the SB5-HC to SB5-LC group was within the acceptance interval of 0.80–1.25. A subgroup analysis was conducted to investigate impact of post-dose ADA status on PK parameters. The post-dose ADA status was defined as positive for subjects with at least one ADA positive test post-baseline, and defined as negative for subjects without any ADA positive test post-baseline. PK parameters were calculated using Phoenix® WinNonlin® version 8.2 (Certara, Palo Alto, CA, USA).

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