Bimekizumab safety in patients with moderate-to-severe plaque psoriasis: pooled data from up to 3 years of treatment in randomized phase III trials

Background Patients with psoriasis require long-term management; therefore, understanding the long-term safety of new treatments, such as bimekizumab (BKZ), is crucial. Objectives To evaluate BKZ’s 3-year safety profile in patients with moderate-to-severe plaque psoriasis. Methods Three years of safety data were pooled

][3][4] Patients with psoriasis have higher risk of type 2 diabetes, hypertension, obesity, inflammatory bowel disease (IBD), anxiety and depression than the general population. 5 -9herefore, assessing long-term safety of psoriasis treatments is essential.
Current moderate-to-severe psoriasis treatment focuses on advanced biologic therapies, such as tumour necrosis factor (TNF)-α and interleukin (IL)-23 and IL-17A inhibitors, which target key cytokines in psoriasis pathogenesis and have well-established safety profiles. 10 -205][26][27] Further investigations have reported long-term maintenance of efficacy with BKZ over 3 years, as indicated by complete/ near-complete skin clearance. 28reviously, 2-year data pooled from phase II and III trials demonstrated that BKZ is well tolerated. 29Here, we report the first 3-year safety data for BKZ in patients with moderate-to-severe plaque psoriasis, pooled from three phase III trials and their open-label extension (OLE).

Patients
26]30 The BE BRIGHT data cutoff was 23 October 2021, the date when the last ongoing patient reached 3 years of study treatment.
5][26] Eligible patients for all trials were adults with moderate-to-severe plaque psoriasis, with baseline Psoriasis Area and Severity Index (PASI) ≥ 12, ≥ 10% body surface area affected by psoriasis and Investigator's Global Assessment ≥ 3 on a 5-point scale, who were eligible for systemic psoriasis therapy and/or phototherapy.
Patients were excluded if they had active symptomatic IBD, recent (< 6 months before screening) myocardial infarction/stroke, high risk of acquiring a tuberculosis (TB) infection (or active TB infection) or active suicidal ideation < 1 month or suicide attempt < 5 years before screening.

Study designs
All studies were conducted in accordance with the principles of the Declaration of Helsinki and approved by an Independent Review Board and Independent Ethics Committee.All participants provided informed written consent.
][26] Upon completion of each trial, patients were eligible to enrol in BE BRIGHT: an ongoing, multicentre, OLE study in which patients received BKZ 320 mg every 4 weeks (Q4W) or every 8 weeks (Q8W), depending on treatment, dose and PASI response at the end of the feeder study (Figure 1).Following protocol amendment, at OLE Week 48 (end of the second year of treatment) or the next scheduled clinic visit, all patients receiving BKZ Q4W switched to Q8W dosing.

Safety evaluations
Treatment-emergent adverse events (TEAEs), serious and severe TEAEs, and TEAEs leading to discontinuation are reported.TEAEs were defined as AEs that occurred during exposure to treatment, including up to 140 days (five half-lives of BKZ) after the last dose was received.Serious TEAEs were TEAEs that led to at least one of the following: death, life-threatening event, substantial/persistent disability or incapacity, congenital anomaly or birth defect, important medical event and initial/prolongation of hospitalization.TEAEs were coded according to MedDRA version 19.0.AE intensity was assessed by investigators as mild, moderate or severe, independently from seriousness.
Predefined cardiovascular, gastrointestinal and neuropsychiatric TEAEs were reviewed and adjudicated by independent Cardiovascular, IBD and Neuropsychiatric Adjudication Committees, respectively.SIB was assessed using the electronic Columbia-Suicide Severity Rating Scale (eC-SSRS). 31pportunistic infections were predefined using company conventions.Patients were screened to evaluate TB signs, symptoms and possible exposure.If a patient had a positive TB test, study treatment was stopped immediately and patients were referred to a TB specialist for further evaluation.

Statistical analysis
Pooled safety data were analysed, using SAS v9.4 (SAS Institute, Cary, NC, USA), for all patients who received at What does this study add?
• Here, we report the first 3-year safety data for BKZ in patients with moderate-to-severe plaque psoriasis, pooled from three phase III trials and their open-label extension.• No new safety signals were observed through 3 years of BKZ treatment.The risk of adverse events either remained consistent or decreased with longer BKZ exposure, and was lower with BKZ every 8 weeks vs. every 4 weeks.
least one BKZ dose in the phase III trials (BKZ Total).Safety data were also analysed separately for BKZ Q4W and Q8W treatment groups.TEAEs were attributed to the treatment and dose most recently received before the onset date.
Exposure-adjusted incidence rates (EAIRs) were used to evaluate TEAEs; EAIRs represent the number of patients with a particular AE adjusted for duration of exposure.EAIRs are reported per 100 patient-years (PY) with associated 95% confidence intervals (CIs).PSOriasis Longitudinal Assessment and Registry (PSOLAR) ranges are reported for TEAEs of interest where available. 32ata are presented for the full pooled trial period for the BKZ Total group and Q4W and Q8W dosing groups, and separately for Years 1 (Weeks 0-52), 2 (Weeks > 52-104) and 3 (Weeks > 104-156) of BKZ exposure for the BKZ Total group.Safety data are also reported through Weeks 0-16 for patients who received BKZ during the initial placebo-or active-controlled trial periods.

Patients
In total, 1495 patients received at least one BKZ dose across the phase III trials (Figure S1; see Supporting Information); baseline characteristics were similar between dosing groups and were representative of patients with plaque psoriasis eligible for biologic therapy (Table S2; see Supporting Information).Total BKZ exposure was 3876.4PY (Q4W, 1965.6 PY; Q8W, 1914.5 PY) and median exposure duration was 1058.0 days (range, 23-1326; Table 1).

Overall safety
The EAIR of TEAEs over 3 years was 175.5/100PY (Table 1) and decreased with each year of BKZ exposure (Figure 2).EAIRs of TEAEs during Weeks 0-16 are also reported in Table 1.EAIRs of TEAEs were numerically lower in patients receiving BKZ Q8W vs. Q4W (Table 1).Serious TEAEs and TEAEs leading to discontinuation occurred at rates of 5.5 and 3.2/100 PY, respectively (Table 1), and did not increase with longer exposure to BKZ (Figure 2).The vast majority of TEAEs were mild or moderate; the EAIR of severe TEAEs was 4.5/100 PY.
The most commonly reported TEAEs across the phase III trials by MedDRA preferred term were nasopharyngitis, oral candidiasis and upper respiratory tract infection, with EAIRs of 15.0, 10.1 and 6.5/100 PY, respectively (Table S3; see Supporting Information).

Deaths
Over 3 years, 16 deaths (0.4/100 PY) were reported (Table 1).None were reported as treatment-related by the investigators.Causes of death were reported under the following preferred terms, each for one patient unless otherwise specified (patients could have multiple preferred terms identified as leading to death): aortic aneurysm rupture, brain neoplasm, cardiac arrest (four patients), cardiopulmonary failure, chronic obstructive pulmonary disease, circulatory collapse, completed suicide, coronavirus infection (three patients), death (two patients, each of unknown cause approximately 3 months after last BKZ dose), haemorrhagic anaemia, hypovolaemic shock and myocardial infarction.

Infections
Over 3 years, the EAIRs of overall infections and serious infections (Table 2) were 81.8 and 1.2/100 PY, respectively; serious infection rates were within the PSOLAR range (0.93-2.91/100PY). 33The most common serious infection was coronavirus (nine events, 0.2/100 PY).Three coronavirus events were fatal (patients had relevant comorbidities and no completed vaccination scheme); no other coronavirus events led to discontinuation.Although 17 patients had concurrent/history of latent TB and received

2.5
(1.7, 3.6) 1.9 (1.1, 3.0)      prophylactic treatment, no patients developed active TB (Table 2).Opportunistic infections had an EAIR of 0.9/100 PY.All were localized mucocutaneous fungal infections predefined as opportunistic, except for one serious case of ophthalmic herpes zoster that resolved with treatment and did not lead to discontinuation.

Candidiasis
The majority of Candida infections were reported as oral candidiasis (10.1/100PY; Table 2).Oral candidiasis EAIRs decreased with longer BKZ exposure (Figure 3), and rates were numerically lower with BKZ Q8W vs. Q4W (Table 2).The vast majority of oral candidiasis events were mild or moderate in severity (99.3%); five were severe, none were serious.One patient receiving BKZ Q4W reported a serious, severe case of oesophageal candidiasis, as previously reported. 29Rates of vulvovaginal candidiasis did not increase with longer BKZ exposure (Table 2).Seven patients discontinued BKZ due to Candida infections; five of these discontinued due to oral candidiasis (three in Year 1; three/ two while receiving Q4W/Q8W dosing, respectively).

Adjudicated inflammatory bowel disease
The 3-year EAIR for adjudicated definite or probable IBD was low (0.2/100 PY; Table 2).EAIRs did not increase with longer exposure to BKZ (Figure 3).In total, seven cases were adjudicated as definite (two Crohn's disease, one ulcerative colitis, one unclassified) or probable IBD (one ulcerative colitis, two undifferentiated).Three patients had a medical history of IBD; one experienced an IBD TEAE.Five cases led to treatment discontinuation and were considered treatment-related by investigators.

Other treatment-emergent adverse events of interest
The EAIR of adjudicated MACE was low (0.6/100 PY) and remained low with longer BKZ exposure (Figure 3).The EAIR for adjudicated SIB was 0.1/100 PY (Table 2) and remained low with longer BKZ exposure (Figure 3).No SIB events were reported in the third year of treatment.One suicidal ideation event and one completed suicide from the first 2 years of treatment were previously reported; neither were treatment-related. 294][35] However, the EAIR of serious infections in this analysis was low (1.2/100PY), did not increase with longer BKZ exposure, and was within the PSOLAR range (0.9-2.9/100 PY). 32Serious infection rates were also comparable with studies investigating other IL-17 inhibitors, such as brodalumab (1.0-1.3/100PY), 20 secukinumab (1.4-1.5/100PY) 18,36 and ixekizumab (1.3-2.3/100PY). 15,19,37The most common serious infection was coronavirus infection, due to the third year of treatment taking place during the COVID-19 pandemic.No patients developed active TB, despite 17 patients having concurrent/ history of latent TB and receiving prophylactic treatment.
9][40][41][42] Furthermore, some individuals have a predisposed greater risk of oral candidiasis, including those who are elderly, smoke or have endocrine disorders or nutritional deficiencies. 43Although oral candidiasis rates with BKZ remain higher than with other IL-17 inhibitors, 19,36,37 EAIRs decreased with longer BKZ exposure, and were numerically lower in patients receiving BKZ Q8W vs. Q4W.Over the 3-year period, the vast majority of oral candidiasis events were mild or moderate (99.3%); few patients who experienced oral candidiasis discontinued as a result (1.5%).
Occurrences of AST and ALT elevations in this analysis did not increase with longer exposure to BKZ; most elevations were transient and few led to discontinuation.These observations were as expected for the study populations as psoriasis is linked to nonalcoholic fatty liver disease, obesity, diabetes and excessive alcohol consumption, 44,45 all of which are known to affect liver function.
Other TEAEs of interest had low EAIRs over the 3-year period, such as MACE (0.6/100 PY) and malignancies (excluding NMSC; 0.5/100 PY).On rare occasion, new onset or exacerbation of IBD has been reported with other IL-17 inhibitors, 46,47 but IBD rates were low with BKZ (0.2/100 PY), and were similar to those reported in previous studies of individuals with psoriasis. 18,19,36,48Those with psoriasis are also at increased risk of depression and SIB; [49][50][51] however, EAIRs of depression and adjudicated SIB were low with BKZ throughout (0.4/100 PY and 0.1/100 PY).
This analysis is strengthened by its long-term nature and large sample size.Furthermore, these long-term safety data show lower TEAE rates with the BKZ Q8W dosing regimen, the recommended maintenance dose for most patients following initial Q4W dosing for 16 weeks, 52 supporting its use in clinical practice.However, as Q8W dosing has been associated with lower rates of certain TEAEs vs. Q4W, 24 and Year 3 data include a greater proportion of patients receiving Q8W dosing than Years 1 and 2, this may have contributed to the lower TEAE rates seen through Year 3. Due to the nature of the OLE, patients were not blinded during this period, so Year 2 and 3 data are subject to reporting bias.Moreover, these findings may be limited in their generalizability to real-world populations, due to minimal racial diversity in the patient populations and stringent patient exclusion criteria.OLE data may also have been affected by the COVID-19 pandemic coinciding with its second year (third year of treatment overall).Potential confounding factors, such as social isolation, mask wearing and lockdowns may have affected TEAE rates, in particular respiratory infections such as nasopharyngitis.
In these analyses pooled across 3 years of treatment from three phase III clinical trials and their OLE, BKZ demonstrated a favourable safety profile, with no new safety signals observed.The risk of AEs either remained consistent or decreased with longer BKZ exposure, and was lower with BKZ Q8W vs. Q4W.

Dose at end of feeder study Open-label treatment period a Placebo Bimekizumab 320 mg Q4W Bimekizumab 320 mg Q8W OLE baseline OLE Week 96 OLE Week 24 OLE Week 48 All patients switched at OLE Week 48 or next scheduled visit d ≥PASI 90 Investigator discretion c
PlaceboFigure1BE BRIGHT study design.All patients who did not achieve PASI 90 at the end of the feeder studies received BKZ 320 mg Q4W upon OLE entry.Patients who were receiving BKZ 320 mg Q8W and achieved PASI 90 remained on Q8W dosing.Patients who were receiving BKZ 320 mg Q4W and achieved PASI 90 were randomized 4 : 1 to receive BKZ 320 mg Q4W or Q8W.Patients who were receiving ustekinumab at the end of BE VIVID and achieved PASI 90 were randomized 1 : 1 to receive BKZ 320 mg Q4W or Q8W.Patients who received BKZ 320 mg Q4W during the initial 16-week treatment period of BE READY and were re-randomized to placebo for the randomized withdrawal period received BKZ 320 mg Q4W upon OLE entry.a Patients who completed the BE VIVID, BE READY or BE SURE phase III trials were eligible to enrol in the BE BRIGHT OLE; b BE VIVID had a duration of 52 weeks, and BE READY and BE SURE had a duration of 56 weeks; c at Week 24 of the BE BRIGHT OLE, patients receiving BKZ 320 mg Q4W who had achieved PASI 90 could be switched to receive BKZ 320 mg Q8W at the discretion of the investigator; d at Week 48 of the OLE, or at the next scheduled clinic visit, all patients who had remained on BKZ 320 mg Q4W were re-assigned to BKZ 320 mg Q8W, via protocol amendment.BKZ, bimekizumab; OLE, open-label extension; PASI, Psoriasis Area and Severity Index; PASI 90, ≥ 90% reduction from baseline in PASI; Q4W, every 4 weeks; Q8W, every 8 weeks; Q12W, every 12 weeks.

Table 1
Summary of treatment exposure and TEAEs in patients treated with BKZ in the phase III trials Data are shown as of the data cut-off date(23 October 2021).Data are pooled from the BE VIVID, BE READY and BE SURE phase III trials and their open-label extension BE BRIGHT.Data are presented for the BKZ Q4W dosing group for the initial 16-week treatment period, BKZ total and Q4W and Q8W dosing groups for the full pooled trial period, and separately for Years 1 (Weeks 0-52), 2 (Weeks > 52-104) and 3 (Weeks > 104-156) of BKZ exposure for the BKZ total group.a BKZ Total includes all patients who received at least one BKZ dose in the included studies; b Patients who received both BKZ 320 mg Q4W and Q8W are included in the population count of both dosing groups, but only once in each BKZ Total group; c Total BKZ exposure over 3 years is greater than the sum of BKZ exposure in individual years, as data beyond Week 156 are included due to the use of a cut-off date.BKZ, bimekizumab; CI, confidence interval; EAIR, exposure-adjusted incidence rate; PY, patient-years; Q4W, every 4 weeks; Q8W, every 8 weeks; SD, standard deviation; TEAE, treatment-emergent adverse event.
Data are shown as of the data cut-off date(23 October 2021).Data are pooled from the BE VIVID, BE READY and BE SURE phase III trials and their open-label extension BE BRIGHT.Data are presented for the BKZ Q4W dosing group for the initial 16-week treatment period, BKZ total and Q4W and Q8W dosing groups for the full pooled trial period, and separately for Years 1 (Weeks 0-52), 2 (Weeks > 52-104) and 3 (Weeks > 104-156) of BKZ exposure for the BKZ total group.a BKZ Total includes all patients who received at least one BKZ dose in the included studies; b Patients who received both BKZ 320 mg Q4W and Q8W are included in the population count of both dosing groups, but only once in each BKZ Total group; c Includes the preferred terms: anal fungal infection, ear infection fungal, fungal oesophagitis, fungal infection, fungal pharyngitis, fungal skin infection, genital infection fungal, onychomycosis, oral fungal infection, oropharyngitis fungal, tongue fungal infection and vulvovaginal mycotic infection; dNo anaphylactic reactions associated with BKZ were reported.ALT, alanine aminotransferase; AST, aspartate aminotransferase; BKZ, bimekizumab; CI, confidence interval; EAIR, exposure-adjusted incidence rate; IBD, inflammatory bowel disease; MACE, major adverse cardiac event; NEC, not elsewhere classified; NMSC, nonmelanoma skin cancer; PY, patient-years; Q4W, every 4 weeks; Q8W, every 8 weeks; SIB, suicidal ideation and behaviour; TEAE, treatment-emergent adverse event; ULN, upper limit of normal.