Switching to Biosimilar SDZ-ADL in Patients with Moderate-to-Severe Active Rheumatoid Arthritis: 48-Week Efficacy, Safety and Immunogenicity Results From the Phase III, Randomized, Double-Blind ADMYRA Study

Abstract

Background: Sandoz adalimumab SDZ-ADL (GP-2017) is an approved adalimumab biosimilar with similar efficacy and comparable safety and immunogenicity to reference adalimumab (ref-ADL) as confirmed by analytical, pharmacokinetic and confirmatory studies. ADMYRA, a phase III double-blind study, was conducted with an aim to generate efficacy, safety and immunogenicity comparability data in patients with moderate-to-severe rheumatoid arthritis (RA) having inadequate response to disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX). The study also evaluated an aspect of 'switching' reference product to the biosimilar in terms of efficacy, safety and immunogenicity up to Week 48.

Methods: Eligible patients (N = 353) were randomized 1:1 to receive subcutaneous (sc) SDZ-ADL 40 mg (n = 177) or ref-ADL (n = 176) every other week from Week 0 to Week 24. At Week 24, all patients with at least a moderate response by Disease Activity Score-28 including high-sensitivity C-reactive protein (DAS28-CRP) in the SDZ-ADL group continued SDZ-ADL (n = 159), and in the ref-ADL group were switched to SDZ-ADL (n = 166), treated for up to 46 weeks. The primary endpoint was change in DAS28-CRP from baseline at Week 12. Other efficacy endpoints included proportion of patients with European League Against Rheumatism (EULAR) response, EULAR remission, Boolean remission, safety and immunogenicity.

Results: The DAS28-CRP score changes from baseline at Week 12 were similar between SDZ-ADL (- 2.16) and ref-ADL (- 2.18) with a mean difference (95% CI) of 0.02 (- 0.24 to 0.27), which was within the pre-specified equivalence margin of ± 0.6. After switching treatment from ref-ADL to SDZ-ADL, the mean DAS28-CRP change was similar between the SDZ-ADL and 'ref-ADL/switched SDZ-ADL' group (- 3.09 vs - 3.05). The proportion of patients with good/moderate EULAR response was 69.2%/29.0% in the SDZ-ADL group and 68.0%/29.6% in the 'ref-ADL/switched SDZ-ADL' group. The proportion of patients in EULAR remission was 51.4% and 54.4% and in Boolean remission was 16.8% and 21.6% for SDZ-ADL and 'ref-ADL/switched SDZ-ADL' groups, respectively. The secondary endpoints were similar across the treatment groups. The incidence of adverse events (AEs) and injection-site reactions were low and similar between SDZ-ADL and 'ref-ADL/switched SDZ-ADL' groups (AEs 70.6% vs 68.8%, injection-site reactions 4.0% vs 6.3%), and most of these patients experienced AEs of mild or moderate severity. Antidrug antibodies were detected in 24.2% and 25.6% of patients treated with SDZ-ADL and 'ref-ADL/switched SDZ-ADL', respectively, from baseline to Week 48, of which 72.5% in SDZ-ADL and 79.1% in 'ref-ADL/switched SDZ-ADL' groups were neutralizing.

Conclusions: In patients with moderate-to-severe RA who had an inadequate response to DMARDs, SDZ-ADL demonstrated a similar efficacy and a comparable safety and immunogenicity profile to ref-ADL. Efficacy was sustained after switching from ref-ADL to SDZ-ADL with no impact on safety (NCT02744755).

Fig. 1

Study design resembled ref-ADL ARMADA trial [25]. Study treatment in Study Period 1: SDZ-ADL or ref-ADL 40 mg/0.8 mL sc injection from Day 1 to W22. Study treatment in Study Period 2: patients with at least moderate EULAR response switched to SDZ-ADL from W24 until W46. In Study Periods 1 and 2, last injections were administered at W22 and W46, respectively; last patient assessments were performed at W24 and W48, respectively. CRP C-reactive protein, DAS disease activity score, EULAR European League Against Rheumatism, Ref-ADL reference adalimumab, sc subcutaneous, SDZ-ADL Sandoz biosimilar adalimumab, W week

Fig. 2

a Mean changes from baseline in DAS28-CRP scores over 12 weeks (W12 PPS). A mixed-model repeated measures analysis was performed for DAS28-CRP change from baseline including treatment, stratification factors, time (visits), the interaction between time (visits) and treatment, all as categorical variables, and baseline DAS28-CRP value as a continuous variable. *One patient had more than two joint assessments missing and therefore DAS28-CRP was not calculated. b Mean change in DAS28-CRP scores over 48 weeks (SP2 PPS). The boxed values represent actual mean values for comparison. At BL, actual mean DAS28-CRP for SDZ-ADL and ref-ADL/switched SDZ-ADL were 5.74 and 5.73, respectively. BL baseline, CI confidence interval, CRP C-reactive protein, DAS disease activity score, LS least squares, N number of patients per treatment group, PPS per-protocol set, ref-ADL reference adalimumab, SD standard deviation, SDZ-ADL Sandoz biosimilar adalimumab, SE standard error, SP2 PPS study period 2 per protocol set: all patients in the SP1 PPS who completed the full study and do not have any major protocol deviations during the entire study

Fig. 3

Proportion of patients achieving EULAR response and proportion of patients with EULAR and Boolean remission over time (SP2 PPS). a EULAR good/moderate responses up to Week 48. b EULAR and Boolean remission up to Week 48. Dotted lines indicate the treatment switch from ref-ADL group to SDZ-ADL group. EULAR European League Against Rheumatism, ref-ADL reference adalimumab, SDZ-ADL Sandoz biosimilar adalimumab, SP2 PPS study period 2 per protocol set, Wk week

Fig. 4

ACR20/50/70 responses over 48 weeks (SP2 PPS). Dotted lines indicate the treatment switch from ref-ADL group to SDZ-ADL group. ACR American College of Rheumatology, ref-ADL reference adalimumab, SDZ Sandoz biosimilar adalimumab, SP2 PPS study period 2 per protocol set, Wk week

Fig. 5

Mean change in CRP and ESR levels over 48 weeks (SP2 PPS). a CRP, b ESR. Dotted lines indicate the treatment switch from ref-ADL group to SDZ-ADL group. CRP C-reactive protein, ESR erythrocyte sedimentation rate, ref-ADL reference adalimumab, SDZ-ADL Sandoz biosimilar adalimumab, SP2 PPS study period 2 per protocol set