Safety, efficacy, and drug survival of biologics and biosimilars for moderate-to-severe plaque psoriasis Alexander Egeberg, MD PhD; Mathias Bo Ottosen, MSc; Robert Gniadecki, MD PhD DMSc; Sigurd Broesby-Olsen, MD; Tomas Norman Dam, MD PhD; Lars Erik Bryld, MD PhD; Mads Rasmussen, MD PhD; Lone Skov, MD PhD DMSc

First and Corresponding author is Alexander Egeberg of Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Denmark.

What’s already known? Aims of current study: Long-term drug survival is dependent on the patient’s sex, choice of drug, and previous exposure to biologics. Ustekinumab has been put forward as the biologic with highest drug survival Real-life data on newer agents such as secukinumab, as well as comparisons between originators and biosimilars are lacking Aims of current study: 1: To examine safety, efficacy, and time to discontinuation (drug survival) of biologics (adalimumab, etanercept, infliximab, secukinumab, and ustekinumab) 2: To compare originators with biosimilars (i.e. Enbrel with Benepali, and Remicade with Remsima).

Methods The DERMBIO registry contains data on all Danish patients with moderate-to-severe plaque psoriasis treated with biologics. We examined patients treated between January 1st, 2007 and March 31st, 2017. We used Kaplan-Meier survival curves and Cox-regression to examine drug survival. Kaplan-Meier curves are presented for biologic-naïve and non-naïve patients, as well as for treatment according to European Medicines Agency (EMA) label. Cox regressions include sex, PsA, and concomitant methotrexate use, and number of previous treatments in adjusted models. For analyses of well-treated patients switching from an originator to a biosimilar, we implemented a robust variance calculation to account for repeated subjects

Results: Baseline characteristics   Adalimumab Etanercept Infliximab Secukinumab Ustekinumab Number of patients 1215 517 296 195 1002 Female, n (%) 439 (36.1) 199 (38.5) 117 (39.5) 84 (43.1) 378 (37.7) Male, n (%) 776 (63.9) 318 (61.5) 179 (60.5) 111 (56.9) 624 (62.3) Age, mean (SD) 45.4 (14.0) 46.5 (15.5) 47.7 (14.0) 48.7 (13.8) 45.0 (14.4) Weight in kg, mean (SD) 88.6 (20.5) 87.4 (21.4) 92.7 (23.2) 93.6 (22.0) 90.6 (22.5) Disease duration in years, mean (SD) 19.9 (12.3) 21.6 (13.5) 22.1 (13.6) 23.2 (11.7) 20.2 (12.2) PsA, n (%) 486 (40.0) 219 (42.4) 144 (48.7) 98 (50.3) 226 (22.6) DLQI, mean (SD) 9.7 (7.6) 8.5 (7.3) 9.1 (7.7) 9.1 (7.4) 10.3 (8.0) PASI at baseline, mean (SD) 9.0 (7.2) 8.9 (8.0) 9.6 (8.5) 7.1 (6.4) 9.4 (7.2) Comorbidities, n (%) 773 (63.6) 317 (61.3) 192 (64.9) 150 (76.9) 734 (73.3) 1 273 (22.5) 124 (24.0) 65 (22.0) 21 (10.8) 167 (16.7) 2 105 (8.6) 49 (9.5) 24 (8.1) 16 (8.2) 64 (6.4) ≥3 64 (5.3) 27 (5.2) 15 (5.1) 8 (4.1) 37 (3.7) Bio-naïve, n (%) 896 (73.7) 364 (52.7) 156 (52.7) 42 (21.5) 541 (54.0) Methotrexate, n (%) 184 (15.1) 44 (8.5) 93 (31.4) 111 (11.1) A patient can be treated multiple times with the same drug. Only the first series in which the patient is exposed to the drug is shown.

Results: Adverse events Incidence rates of adverse events per 100 treatment-years

Results Failures due to lack of efficacy Only biologic naïve patients Only non-biologic naïve patients Treatment according to EMA label* EMA = European Medicines Agency * In this analysis, patients are also considered to have failed therapy if their biologic dosing is increased to higher-than-approved levels (dose escalation or shortening of the treatment interval). For each week, assessment is made based on whether the cumulative dose in the past twelve weeks exceed the approved EMA-label dosing.

Risk of all-cause discontinuation Results Forest plot of adjusted (sex, PsA, concomitant methotrexate, and number of previous treatments) hazard ratios for risk of all-cause drug discontinuation in all treatment series. Estimates listed on the right side of the vertical line favors the drug listed on the right, and vice versa Example 1: ustekinumab is superior to infliximab (result in top row) Example 2: adalimumab is superior to secukinumab (result in bottom row)

Results Proportion of series that were discontinued Cause-specific discontinuation

Switching of well-treated patients from originators to biosimilars Results Switching of well-treated patients from originators to biosimilars Enbrel and Benepali Remicade and Remsima Risk of discontinuation HR 0.46, 95% CI 0.11-1.98, p=0.297 Risk of discontinuation HR 1.64, 95% CI 0.69-3.89, p=0.264 Cox proportional hazards regression with a robust variance calculation was implemented to account for repeated subjects

Discussion What does this study add? This study provides long-term safety, efficacy, and drug survival data on anti-IL-12/23 and anti-TNF agents for moderate-to-severe psoriasis, and data on outcomes from more than two years of real-life treatment with secukinumab. The study also compared drug survival between original and biosimilar versions of etanercept and infliximab among patients with psoriasis. Biologic registries are valuable tools to examine adverse events and monitor safety signals of rare outcomes, but direct between-drug comparisons should be cautioned, since patient characteristics, underlying considerations for choice of therapy, and study results from a real-life settings may differ considerably from that of randomized clinical trials

Conclusions Ustekinumab was associated with the longest drug survival, whereas the shortest was seen with secukinumab Treatment according to EMA label yielded longest drug survival with ustekinumab, followed by adalimumab Switching from originator to biosimilar infliximab or etanercept had no significant impact on retention rates Adverse events were most frequent for secukinumab (predominantly infections) Cardiovascular events were rare, but occurred slightly more frequent with secukinumab These findings may affect choice of therapy for candidates for biologic therapy, including both bio-naïve and currently well-treated patients, as well as those who have failed on one or more biologic agents.

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