Phase III randomized study of the proposed adalimumab biosimilar GP2017 in psoriasis: impact of multiple switches A. Blauvelt,1 J.-P. Lacour,2 J. F. Fowler Jr,3 J. M. Weinberg,4 D. Gospodinov,5 E. Schuck,6 J. Jauch-Lembach,6 A. Balfour6 and C. L. Leonardi7 1Oregon Medical Research Center, Portland, OR, U.S.A.; 2University of Nice Sophia Antipolis, Nice, France; 3Dermatology Specialists, Louisville, KY, U.S.A.; 4Mount Sinai School of Medicine, New York, NY, U.S.A.; 5Medical University, Pleven, Bulgaria; 6Hexal AG, Holzkirchen, Germany British Journal of Dermatology. DOI: 10.111/bjd.16890

Introduction What’s already known? Adalimumab is indicated for use in psoriatic arthritis, plaque psoriasis, and hidradenitis suppurativa GP2017 is a biosimilar to adalimumab. Previous studies have shown that GP2017 and adalimumab have identical chemical structures and the same level of post-translational modifications and similar in vitro functionality1,2 This study compared efficacy and safety of GP2017 with reference adalimumab and assessed impact of multiple switches between GP2017 and reference adalimumab on efficacy, safety and immunogenicity in adult patients with moderate-to-severe plaque psoriasis 1. Schiestl M, Roesli C. Am J Gastroenterol 2016; 111:S289 (Abstract 628). 2.. Kronthaler U, et al. Exp Opin Biol Ther 2018; 18:921–30. GP2017, Sandoz biosimilar adalimumab.

Objective The primary objective of the study was to demonstrate equivalent efficacy for GP2017 and reference adalimumab in terms of the proportion of patients who achieved PASI 75 at week 16 The key secondary objective was to compare the percent change from baseline in continuous PASI up to week 16 Other objectives included: PASI over time, IGA of disease activity, pharmacokinetics, safety, tolerability and immunogenicity for the switched and continued treatment groups GP2017, Sandoz biosimilar adalimumab; IGA, investigator global assessment; PASI, Psoriasis Area and Severity Index; TP, treatment period.

Multicenter, randomized, double-blind, comparator-controlled phase III confirmatory study with four study periods Treatment period 1 Treatment period 2 Screening Extension period GP2017 GP2017 GP2017 ref-ADMB GP2017 ref-ADMB GP2017 Switched groups W17–W51 Continued groups Randomization to W51 GP2017 ref-ADMB GP2017 ref-ADMB ref-ADMB ref-ADMB ref-ADMB This was a randomized, multicentre, phase III, confirmatory study consisting of four periods: screening treatment period 1 (randomisation to week 17) treatment period 2 (weeks 17–35) extension period (weeks 35–51) Day 1 Randomization Week 17 Re-randomization Week 23 Week 29 Week 35 Week 51 End of study Week 16 Analysis of primary endpoint GP2017, Sandoz biosimilar adalimumab; ref-ADMB, reference adalimumab; W, week.

ADACCESS: Key efficacy results Logistic regression analysis on PASI 75 response at week 16 (primary end point)   Patients, n Patients with PASI 75 response at week 16, n Adjusted response rate, % ± SE Adjusted response rate Δ, % ± SE 95% CI* Analysis on per protocol set GP2017 197 132 66·8 ± 3·33 1·8 ± 4·75 –7·46, 11·15 Ref-ADMB 196 127 65·0 ± 3·38 Supportive analysis on full analysis set 231 134 58·1 ± 3·23 2·2 ± 4·56 –6·79, 11·10 234 131 55·9 ± 3·23 Mean % change from baseline in PASI score was similar over time Continued ref-ADMB (TP1, n = 197; TP2 + EP, n = 115) ref-ADMB to GP2017 (n = 51) -20 Continued GP2017 (TP1, n = 197; TP2 + EP n = 105) GP2017 to ref-ADMB (n = 55) -40 Mean change in PASI score from baseline, % -60 -80 -100 17 23 29 35 41 47 51 The primary and key secondary objectives of the study were met (Table). As 95% CI were contained within prespecified margins, equivalent efficacy between GP2017 and ref-ADMB was confirmed in both the per protocol set and full analysis set. No significant differences were observed in subgroups of patients who had or had not received prior systemic therapy.   Mean percent change in PASI from baseline was similar between the GP2017 and ref-ADMB treatment groups (during TP1) and in the switched and continued treatment groups from Week 17–51 (after re-randomization). Similar results were seen for PASI50, 75, 90 and 100 response rates (data not shown). Time, weeks TP1 TP2 EP Re-randomization *Equivalence margin of ± 18%. CI, confidence interval; EP, extension period; GP2017, Sandoz biosimilar adalimumab; PASI, Psoriasis Area and Severity Index; ref-ADMB, reference adalimumab; SE, standard error; TP, treatment period.

ADACCESS: Safety results   TP1 (Randomization to Week 17) TP2 + EP (Week 17 to Week 51) Patients, n (%) ref-ADMB (n = 234) GP2017 (n = 231) Continued ref- ADMB (n = 127) ref-ADMB to GP2017 (n = 63) Continued GP2017 (n = 126) GP2017 to ref- ADMB (n = 63) ≥ 1 AE 123 (52·6) 116 (50·2) 71 (55·9) 29 (46·0) 66 (52·4) 36 (57·1) Mild 68 (29·1) 72 (31·2) 33 (26·0) 11 (17·5) 26 (20·6) 23 (36·5) Moderate 45 (19·2) 41 (17·7) 31 (24·4) 14 (22·2) 37 (29·4) 12 (19·0) Severe 10 (4·3) 3 (1·3) 7 (5·5) 4 (6) 3 (2·4) 1 (2) ≥ 1 SAE 8 (6·3) 2 (3) ≥ 1 treatment-related AE 28 (12·0) 33 (14·3) 16 (12·6) 10 (16) 16 (12·7) 9 (14·3) ≥ 1 treatment-related SAE 1 (0·4) 1 (0·8) ≥ 1 AE of special interest† 17 (7·3) 13 (5·6) 12 (9·4) 3 (5) 7 (5·6) 6 (10) ≥ 1 ISR 8 (3·4) 15 (6·5) 5 (3·9) 4 (3·2) AE leading to treatment interruption 4 (1·7) 5 (2·2) 14 (11·1) 5 (8) AE leading to treatment discontinuation 7 (3·0) Deaths †Encompasses all the warnings and precautions given in the label for reference adalimumab, including infections, malignancy, allergic/anaphylactic reactions, immune system disorders/autoimmune events, neurological events, haematological events, congestive heart failure and interstitial lung disease. AE, adverse event; EP, extension period; GP2017, Sandoz biosimilar adalimumab; ISR, injection site reaction; ref-ADMB, reference adalimumab; SAE, serious adverse event; TP, treatment period.

ADACCESS: Immunogenicity   TP1 (Randomization to week 17) TP2 + EP (week 17 to week 51) ref-ADMB (n = 234) GP2017 (n = 231) Continued ref- ADMB (n = 127) ref-ADMB to GP2017 (n = 63) Continued GP2017 (n = 126) GP2017 to ref- ADMB (n = 63) Overall antidrug antibody response, n/n (%) Negative 145/220 (65·9) 139/220 (63·2) 67/122 (54·9) 37/61 (61) 79/123 (64·2) 32/60 (53) Positive 75/220 (34·1) 81/220 (36·8) 55/122 (45·1) 24/61 (39) 44/123 (35·8) 28/60 (47) Neutralizing 60/75 (80) 65/81 (80) 47/55 (85) 24/24 (100) 38/44 (86) 21/28 (75) In the switched and continued treatment groups, neutralizing antibodies were detected in 75–100% of patients positive for antidrug antibodies EP, extension period; GP2017, Sandoz biosimilar adalimumab; ref-ADMB, reference adalimumab; TP, treatment period.

Discussion The results of this study contributed to the to evidence established from previous analytical, preclinical and pharmacokinetic studies,1–3 which are supportive for claiming biosimilarity between GP2017 and reference adalimumab Generation of data, either in clinical trials assessing the impact of multiple switches between a reference medicine and biosimilar or real-world data, would be beneficial to continue to address possible concerns of clinicians when prescribing biosimilars 1. Schiestl M, Roesli C. Am J Gastroenterol 2016; 111:S289 (Abstract 628). 2. Kronthaler U, et al. Exp Opin Biol Ther 2018; 18:921–30. 3. Jauch-Lembach J, et al. Arthritis Rheum 2017; 69(suppl 10):Abstract 2443. GP2017, Sandoz biosimilar adalimumab.

Conclusions What does this study add? This phase III confirmatory study demonstrated equivalent efficacy and similar safety of GP2017 and reference adalimumab in patients with moderate-to-severe plaque psoriasis Switching up to four times between GP2017 and reference adalimumab had no impact on efficacy, the incidence of adverse events or injection site reactions The frequency of anti-drug antibody development was similar across switched and continued treatment groups GP2017, Sandoz biosimilar adalimumab

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