Comparison of the pharmacokinetics, safety, and immunogenicity of MSB11022, a biosimilar of adalimumab, with Humira(®) in healthy subjects.

The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of the proposed adalimumab biosimilar MSB11022 (Merck) with Humira(®) (AbbVie), sourced from both the US (US reference product [US-RP]) and Europe (European reference medicinal product [EU-RMP]). In this phase 1 double-blind, parallel group trial (EMR200588-001), 213 healthy volunteers were randomized 1 : 1 : 1 to receive a single dose (40 mg) of MSB11022, US-RP or EU-RMP in order to achieve 80% power assuming a 5% difference among groups and a 10% dropout rate. Following a preplanned blinded sample size re-assessment after more than 50% of the originally planned subjects had been observed, the sample size was increased to 237 (79 per arm) to ensure 213 completers. Primary PK endpoints analyzed by non-compartmental methods, were area under the curve (AUC) from time 0 extrapolated to infinity (AUC(0,∞)), maximum observed concentration (Cmax ), and AUC from time 0 to the last quantifiable concentration (AUC(0,tlast )). PK equivalence was declared if the 90% CI for the test : reference ratio lay within the 80-125% equivalence margin. Bioequivalence was demonstrated if all three PK parameters met the PK equivalence criteria. Safety and tolerability were also evaluated. Mean serum concentration-time profiles for the three treatments were similar. MSB11022 demonstrated PK equivalence to US-RP and EU-RMP for all primary endpoints. The geometric means of AUC(0,∞), Cmax and AUC(0,tlast ) following a single dose of MSB11022 were 2276.05 μg ml(-1)  h, 3.44 μg ml(-1)   and 1983.90 μg ml(-1)  h, respectively. Adverse events (AEs) were similar across all groups, with treatment-emergent AEs (TEAEs) reported by 62.8%, 56.3% and 62.0% of subjects within the MSB11022, US-RP and EU-RMP groups, respectively. Most of the TEAEs were considered mild and unrelated to study drug. No deaths or severe AEs related to the study drug were reported. Bioequivalence between MSB11022, US-RP and EU-RMP was demonstrated. Safety, tolerability and immunogenicity profiles were similar between subjects receiving MSB11022 and US-RP or EU-RMP. These data support the further clinical evaluation of MSB11022 as a proposed biosimilar of adalimumab.

Hyland E ，Mant T ，Vlachos P ，Attkins N ，Ullmann M ，Roy S ，Wagner V ... -  《-》

Pharmacokinetic equivalence, comparable safety, and immunogenicity of an adalimumab biosimilar product (M923) to Humira in healthy subjects.

The aims of this randomized, double-blind, three-arm, single-dose study were to demonstrate pharmacokinetic (PK) equivalence of the adalimumab biosimilar M923 (hereafter referred to as "M923") to each of 2 reference products, and to assess M923's safety and immunogenicity. Primary PK endpoints were maximum observed concentration (Cmax ), area under the curve (AUC) from time 0 extrapolated to infinity (AUC0-inf ), and AUC from time 0 to 336 hours (AUC0-336 ). Secondary endpoints included safety and immunogenicity assessments. Healthy subjects were randomized 1:1:1 to receive a 40-mg dose of M923 (n = 107); adalimumab US Humira (n = 105), hereafter referred to as "US Humira"; or adalimumab EU Humira (n = 103), hereafter referred to as "EU Humira." PK equivalence was demonstrated for all primary PK endpoints. Geometric least squares means ratios (GMRs) for Cmax , AUC0-inf , and AUC0-336 were 99.4, 100.9, and 100.5, respectively, between the M923 and EU Humira arms and 102.6, 104.2, and 102.9 between the M923 and US Humira arms. The 90% confidence intervals of the GMRs for all PK endpoints were within prespecified confidence bounds of 80%-125%. Adverse event rates were similar across the M923 (47.7%), US Humira (50.9%), and EU Humira (53.3%) arms and were generally mild (73.7%) or moderate (22.0%). The proportion of subjects with a confirmed antidrug antibody (ADA) response was similar across study arms. This study demonstrated bioequivalent PK among M923, US Humira, and EU Humira and demonstrated that the PK parameters were consistent with similar safety and tolerability profile and ADA response rates.

Hillson J ，Mant T ，Rosano M ，Huntenburg C ，Alai-Safar M ，Darne S ，Palmer D ，Pavlova BG ，Doralt J ，Reeve R ，Goel N ，Weilert D ，Rhyne PW ，Chance K ，Caminis J ，Roach J ，Ganguly T ... -  《Pharmacology Research & Perspectives》

A comparative pharmacokinetic study of DRL_BZ, a candidate biosimilar of bevacizumab, with Avastin(®) (EU and US) in healthy male subjects.

The aim of this study was to compare the pharmacokinetics (PK) of DRL_BZ with that of EU-approved (reference medicinal product; RMP) and US-licensed (reference product; RP) bevacizumab (Avastin® ) in healthy male subjects. In this double-blind, parallel-group, Phase 1 study (BZ-01-001), men aged 20-45 years were randomized 1:1:1 to receive a single intravenous infusion of 1 mg kg-1 of bevacizumab as DRL_BZ, RMP or RP. A total of 149 subjects were randomized (DRL_BZ, 50; RMP, 50; RP, 49). Primary endpoints included maximum observed serum concentration (Cmax ), area under the concentration-time curve from time zero (pre-dose) extrapolated to infinity (AUC(0-∞) ), and area under the concentration-time curve from time zero (pre-dose) to last quantifiable concentration (AUC(0-t) ). Secondary objectives were to compare the safety and immunogenicity of DRL_BZ with those of the reference products. Primary PK parameters were comparable across groups, and 90% confidence intervals for the geometric mean ratios of the primary PK endpoints were within the pre-specified equivalence margins (80-125%) for all pairwise comparisons (DRL_BZ vs. RMP, DRL_BZ vs. RP and RMP vs. RP). No deaths or serious adverse events were reported. Similar numbers of subjects reported similar numbers of treatment-emergent adverse events in the three treatment groups. One subject who received DRL_BZ had anti-drug antibodies at the Day 85 visit; however, no anti-drug antibodies were detected in this subject at the 12-month follow-up visit. PK, safety and immunogenicity of DRL_BZ were comparable to EU-approved and US-licensed bevacizumab in healthy male subjects.

Wynne C ，Schwabe C ，Batra SS ，Lopez-Lazaro L ，Kankanwadi S ... -  《-》

Bioequivalence, safety and immunogenicity of BI 695501, an adalimumab biosimilar candidate, compared with the reference biologic in a randomized, double-blind, active comparator phase I clinical study (VOLTAIRE®-PK) in healthy subjects.

Wynne C ，Altendorfer M ，Sonderegger I ，Gheyle L ，Ellis-Pegler R ，Buschke S ，Lang B ，Assudani D ，Athalye S ，Czeloth N ... -  《-》

AURIEL-PsO: a randomized, double-blind phase III equivalence trial to demonstrate the clinical similarity of the proposed biosimilar MSB11022 to reference adalimumab in patients with moderate-to-severe chronic plaque-type psoriasis.

MSB11022 is a proposed adalimumab biosimilar. To compare the efficacy, safety and immunogenicity of MSB11022 with reference adalimumab. AURIEL-PsO was a double-blind randomized controlled equivalence trial, in which patients with moderate-to-severe chronic plaque-type psoriasis were randomized 1 : 1 to MSB11022 or reference adalimumab. The primary end point was ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with a prespecified equivalence interval of ± 18%. Patients with a ≥50% improvement in PASI at week 16 were eligible to enter a double-blind extension period: patients receiving MSB11022 continued treatment, and patients receiving reference adalimumab were rerandomized 1 : 1 either to continue reference adalimumab or to switch to MSB11022. Other efficacy end points and safety, immunogenicity and pharmacokinetic parameters were evaluated at scheduled visits up to weeks 52 (efficacy and immunogenicity), 54 and 66 (safety). In total, 443 patients were randomized. The difference in PASI 75 response rates at week 16 between the treatment arms was -1·9%, and the 95% confidence interval (-7·8% to 4·1%) was within the prespecified equivalence interval. No notable difference in the incidence of treatment-emergent adverse events was observed between treatment arms up to the end of the trial, and no new safety signals were observed. Following treatment switch at week 16, no clinically meaningful differences in safety or immunogenicity were seen between treatment arms through to the end of the observation period. Therapeutic equivalence between MSB11022 and reference adalimumab was demonstrated. AURIEL-PsO provides evidence to support the similarity of both products with regard to efficacy, safety and immunogenicity. What's already known about this topic? Adalimumab is a fully human antitumour necrosis factor-α monoclonal antibody, indicated for the treatment of multiple inflammatory disorders, including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel diseases and ankylosing spondylitis. MSB11022 is a proposed adalimumab biosimilar that has shown structural and functional similarity to the reference product in an extensive analytical comparability exercise. MSB11022 has demonstrated bioequivalence and comparable safety and immunogenicity profiles in a phase I study in healthy volunteers. What does this study add? This phase III study confirmed equivalent efficacy for MSB11022 and reference adalimumab in patients without any immunomodulation comedication in moderate-to-severe chronic plaque-type psoriasis at week 16. The efficacy, safety and immunogenicity of MSB11022 and reference adalimumab were similar over the respective observation periods (week 52 for efficacy and immunogenicity, week 66 for safety). A switch from reference adalimumab to MSB11022 at week 16 did not impact efficacy, safety or immunogenicity.

Hercogová J ，Papp KA ，Chyrok V ，Ullmann M ，Vlachos P ，Edwards CJ ... -  《-》