Complete methodologies were reported to week 16/24 in the primary publications of BE OPTIMAL and BE COMPLETE [24, 25], and further details can be found in the subsequent 1-year publications [20, 21]. All studies assessed subcutaneous bimekizumab 160 mg every 4 weeks (Q4W) in patients with active PsA who met the CASPAR criteria [26].

In brief, BE OPTIMAL (NCT03895203; ClinicalTrials.gov) was a 52-week, phase 3, multicenter, randomized, double‑blind, placebo‑controlled, active reference study of bDMARD-naïve patients with active PsA. The study comprised a 16-week placebo‑controlled, double‑blind period followed by a 36-week active treatment‑blind period. A reference arm (adalimumab 40 mg every 2 weeks [Q2W]) was included to provide a standard-of-care reference for bimekizumab treatment. Patients were randomized 3:2:1 to bimekizumab 160 mg Q4W, placebo or reference (adalimumab 40 mg Q2W). From week 16, placebo‑randomized patients received bimekizumab 160 mg Q4W.

BE COMPLETE (NCT03896581; ClinicalTrials.gov) was a 16-week, phase 3, multicenter, randomized, double-‍blind, placebo-controlled study of patients with active PsA and prior TNFi-IR. Patients were randomized 2:1 to bimekizumab 160 mg Q4W or placebo.

BE VITAL (NCT04009499; ClinicalTrials.gov) is a multicenter, OLE study of patients with active PsA who completed week 52 of BE OPTIMAL or week 16 of BE COMPLETE and met eligibility criteria. The study commenced on 13th August 2019 and is ongoing. All patients that entered the BE VITAL OLE received bimekizumab 160 mg Q4W, regardless of feeder study or prior randomization. Patients randomized to the reference arm in BE OPTIMAL switched to receive bimekizumab 160 mg Q4W at week 52 regardless of treatment response. There was no washout period for patients randomized to adalimumab who switched to bimekizumab. The OLE included up to 140 weeks of treatment (Treatment Period) for all subjects in all countries. Following the completion of, or early withdrawal from the Treatment Period, patients returned for a safety follow-‍up visit 20 weeks after their last dose of bimekizumab. Study designs can be found in Fig. 1.

BE OPTIMAL and BE COMPLETE study designs. The ADA 40 mg Q2W treatment arm served as an active reference. The BE OPTIMAL study was not powered for statistical comparisons of ADA to BKZ or PBO. Completion rates include patients that completed to week 52/104 in BE OPTIMAL and week 52/100 in BE COMPLETE not on randomized treatment (BE OPTIMAL week 52: 9 [1.1%], week 104: 8 [0.9%]; BE COMPLETE week 52: 4 [1.0%], week 100: 2 [0.5%]). 2 patients in BE COMPLETE were classified as ongoing at week 52 as they did not have a visit for week 52 but no formal discontinuation reason was reported. ACR50‍ ≥ 50% improvement in American College of Rheumatology response criteria, ADA ‍adalimumab, bDMARD biologic disease-‍modifying antirheumatic drug, BKZ bimekizumab, OLE open-label extension, PBO placebo, TNFi-IR prior inadequate response or intolerance to tumor necrosis factor inhibitors

Study visits occurred Q4W from the Entry Visit (week 0 of the BE VITAL OLE) to week 12, then every 12 weeks thereafter up to week 140. In some countries, this was extended past week 140. Bimekizumab could be self-administered after week 12, as patients were required to attend study visits less frequently. Patients could still attend Q4W to receive bimekizumab if self-‍administration was not possible; study outcomes were not collected at these visits.

Inclusion and exclusion criteria for BE OPTIMAL and BE COMPLETE have been reported previously [24, 25]. Patients in both studies were recruited during the same period of time at overlapping study sites and countries. In BE OPTIMAL, patients with current or prior exposure to any biologics for the treatment of PsA or psoriasis were excluded. In BE COMPLETE, patients were required to have had a prior inadequate response or intolerance to one or two TNFis for either PsA or psoriasis; patients with current or previous exposure to any other biologics were excluded. Patients with a prior history of uveitis and/or inflammatory bowel disease were not excluded from either study.

To be eligible for enrollment in the BE VITAL OLE, patients must have completed either week 52 of BE OPTIMAL or week 16 of BE COMPLETE, been expected to benefit from the OLE per the investigator’s discretion, not met any withdrawal criteria in either feeder study, and provided separate informed consent for the OLE.

Studies were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization guidance for Good Clinical Practice. Ethical approval was obtained from the relevant institutional review boards at participating sites, and all patients provided written informed consent in accordance with local requirements. Local institutional review board information can be found in Supplementary Appendix S1.

The primary objective of the BE VITAL OLE was to assess the long-term safety and tolerability of bimekizumab in adult patients with PsA over a period of up to 140 weeks. The secondary objective was to assess the long-term efficacy of bimekizumab.

Safety and efficacy outcomes are reported as the number of weeks from baseline of BE OPTIMAL and BE COMPLETE. Safety outcomes are presented by treatment group and by study period (week 0–52 or week 52–104), and efficacy outcomes are presented by randomization group (placebo-randomized, bimekizumab-randomized, and reference [adalimumab]-randomized [BE OPTIMAL only]). Results are reported by study; results for patients originally enrolled in BE OPTIMAL or BE COMPLETE are hereafter referred to as ‘BE OPTIMAL’ or ‘BE COMPLETE’, respectively.

Safety outcomes, reported from week 0 to 52 and week 52 to week 104, include treatment-emergent adverse events (TEAEs), serious TEAEs, and study discontinuations due to TEAEs. Other safety results reported include drug-related TEAEs, severe TEAEs, deaths, and other safety topics of interest (major adverse cardiovascular events [MACE], neutropenia, serious infections, fungal infections, hypersensitivity, injection site reactions, suicidal ideation and behavior, malignancies, inflammatory bowel disease [IBD] and liver function test changes/enzyme elevations). A serious adverse event must meet one or more of the following criteria: death, life-threatening event, significant or persistent disability/incapacity, congenital anomaly/birth defect (including that occurring in a fetus), initial inpatient hospitalization or prolongation of hospitalization, or an important medical event that (based on appropriate medical judgement) may jeopardize the patient and may require surgical intervention to prevent one of the other outcomes listed. A severe TEAE relates to the intensity of a TEAE, which are reported as either mild, moderate or severe based on clinical classification. A TEAE can be severe, but not considered a serious TEAE if it does not meet any of the abovementioned criteria. MACE, suicidal ideation and behavior, hepatic events and IBD events were adjudicated by an external committee.

Clinical efficacy outcomes, assessed through week 104/100 (BE OPTIMAL/BE COMPLETE), included improvements from baseline of ≥ 20%, ≥ 50%, and ≥ 70% in the American College of Rheumatology response criteria (ACR20/50/70) [27], improvements from baseline of ≥ 75%, ≥ 90%, and 100% in the Psoriasis Area and Severity Index (PASI75/90/100, in patients with psoriasis affecting ≥ 3% body surface area [BSA]) [28] and ACR50 + PASI100 (in patients with psoriasis affecting ≥ 3% BSA).

Achievement of minimal and very low disease activity (MDA, VLDA; achievement of ≥ 5/7 or 7/7, respectively, of the following criteria: tender joint count [TJC] ≤ 1, swollen joint count [SJC] ≤ 1, either PASI ≤ 1 or BSA ≤ 3%, Patient’s Assessment of Arthritis Pain visual analogue scale [Pain VAS] ≤ 15, Patient’s Global Assessment of PsA [PGA‑PsA-VAS] ≤ 20, Health Assessment Questionnaire‑Disability Index [HAQ-‍DI] ≤ 0.5 [29], and tender entheseal points ≤ 1 [measured with the Leeds Enthesitis Index, LEI]) [30], as well as resolution of TJC, SJC, enthesitis (LEI = 0), dactylitis (Leeds Dactylitis Index [LDI] = 0) [31] and nail psoriasis (modified Nail Psoriasis Severity Index [mNAPSI] = 0) were also assessed to week 104/100. Other assessed efficacy outcomes were PASI ≤ 1 responders, Disease Activity Index for Psoriatic Arthritis (DAPSA) high disease activity (HDA), moderate disease activity (MoDA), low disease activity (LDA) and remission (REM) [32], and Psoriatic Arthritis Disease Activity Score (PASDAS) REM and LDA [33].

Patient-reported outcomes (PROs) assessed through week 104/88 include the HAQ-‍DI change from baseline (CfB) and minimal clinically important difference (MCID; decrease from baseline of ≥ 0.35 in patients with baseline score of ≥ 0.35), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) total score CfB, the Pain VAS CfB and ≥ 30/50% improvement thresholds, the 12-‍item Psoriatic Arthritis Impact of Disease (PsAID-‍12) questionnaire total score CfB and MCID (decrease from baseline ≥ 3 in patients with PsAID-12 ≥ 3 at baseline), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) CfB and MCID (CfB ≥ 4 in patients with FACIT-Fatigue subscale ≤ 48 at baseline) and the Short-Form 36-‍item Health Survey Physical Component Summary (SF-36 PCS) CfB.

Statistical powering and sample size determination for BE OPTIMAL and BE COMPLETE were reported in the primary publications [24, 25]. There was no formal sample size for the BE VITAL OLE, as it was determined by the number of patients eligible for entry to the study.

Descriptive statistics are used to provide an overview of the safety and efficacy results. Baseline values for efficacy variables were determined from baseline values of the respective feeder studies (week 0), as per the EULAR guidance for reporting clinical trial extension data [34].

The Safety Set consisted of all randomized patients who received at least one dose of bimekizumab. Safety variables were analyzed for all patients in the Safety Set. Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA version 19.0). Safety outcomes are reported as exposure-‍‍‍adjusted incidence rates (EAIRs) per 100 patient-years (PY) of exposure, with associated 95% confidence intervals (95% CI).

The Randomized Set consisted of all enrolled patients randomized in either feeder study. Efficacy variables were analyzed for all patients in the Randomized Set and reported here by treatment group at initial randomization.

Non-responder imputation (NRI) was used to impute missing data for binary outcomes and multiple imputation was used to impute missing data for continuous outcomes. For categorical data, worst-category imputation was used. Data were imputed using baseline patient numbers from randomization of the feeder studies. Any patients that did not enter the BE VITAL OLE were imputed as non-responders, as per the EULAR guidance for reporting clinical trial extension data [34]. Observed case (OC) data are also reported for binary outcomes. All analyses were done with SAS, version 9.3 or higher.