Safety of guselkumab treatment for up to 5 years in patients with moderate-to-severe psoriasis: pooled analyses across seven clinical trials with more than 8600 patient-years of exposure

Overview of randomized controlled trials of psoriasis included in integrated guselkumab safety analyses

Study, phase, identifier (dates)	Treatment groups (number of randomized patients)
X-PLORE, phase II, NCT01483599 (October 2011–August 2013)¹¹	Placebo (weeks 0, 4, 8) → GUS 100 mg at week 16, then Q8W through week 40 (n = 42) GUS 5 mg at weeks 0, 4 and 16, then Q12W through week 40 (n = 41) GUS 15 mg at weeks 0, 8 and 16, then Q8W through week 40 (n = 41) GUS 50 mg at weeks 0, 4 and 16, then Q12W through week 40 (n = 42) GUS 100 mg at weeks 0, 8 and 16, then Q8W through week 40 (n = 42) GUS 200 mg at weeks 0, 4 and 16, then Q12W through week 40 (n = 42) ADA 80 mg at week 0, 40 mg at week 1, then 40 mg Q2W through week 39 (n = 43)
VOYAGE 1, phase III, NCT02207231 (December 2014–June 2020)⁸	Placebo (weeks 0, 4, 12) → GUS 100 mg at weeks 16 and 20, and Q8W through week 252 (n = 174) GUS 100 mg at weeks 0, 4 and 12, and Q8W through week 252 (n = 329) ADA 80 mg at week 0, 40 mg at week 1 and Q2W through week 47 → GUS 100 mg at week 52 and Q8W through week 252 (n = 334)
VOYAGE 2, phase III, NCT02207244 (November 2014–July 2020)⁸	Placebo (weeks 0, 4, 12) → GUS 100 mg at week 16, 20 (n = 248) PASI 90 nonresponders at week 28 continued GUS 100 mg Q8W PASI 90 responders at week 28 were switched to placebo. Upon loss of ≥ 50% of week 28 PASI response or at week 72, patients were retreated with GUS 100 mg, a 100-mg dose 4 weeks later, then Q8W GUS 100 mg at weeks 0, 4, 12 and 20 (n = 496) PASI 90 nonresponders at week 28 continued GUS 100 mg Q8W PASI 90 responders at week 28 were re-randomized 1 : 1 to: GUS 100 mg Q8W Placebo; upon loss of ≥ 50% of week 28 PASI response or at week 72, patients were retreated with GUS 100 mg, a 100-mg dose 4 weeks later, then Q8W ADA 80 mg at week 0, 40 mg at week 1 and Q2W through week 23 (n = 248) PASI 90 nonresponders at week 28 continued GUS 100 mg Q8W PASI 90 responders at week 28 were switched to placebo. Upon loss of ≥ 50% of week 28 PASI response or at week 72, patients were retreated with GUS 100 mg, a 100-mg dose 4 weeks later, then Q8W All patients received open-label GUS 100 mg Q8W from week 76 to 252
NAVIGATE, phase III, NCT02203032 (October 2014–May 2016)¹⁴	All patients received open-label ustekinumab 45 or 90 mg at weeks 0 and 4. IGA was assessed at week 16; scores were used to assign blinded active treatment as follows: IGA ≥ 2: randomized 1 : 1 to: GUS 100 mg at weeks 16 and 20, then Q8W through week 44 (n = 135) Continue ustekinumab Q12W through week 40 (n = 133) IGA 0/1: continue ustekinumab Q12W through week 40 (n = 585)
ORION, phase III, NCT02905331 (March 2017–February 2018)¹⁵	Placebo (weeks 0, 4, 12) → GUS 100 mg (weeks 16, 20, 28) (n = 16) GUS 100 mg (weeks 0, 4, 12, 20, 28); placebo at week 16 to maintain blinding (n = 62)
ECLIPSE, phase III, NCT03090100 (April 2017–September 2018)¹⁶	GUS 100 mg at weeks 0, 4 and 12, then Q8W through week 44 (n = 534) Secukinumab 300 mg at weeks 0, 1, 2, 3 and 4, then Q4W through week 44 (n = 514)
Japan registration, phase III, NCT02325219 (January 2015–February 2019)¹⁷	Placebo (weeks 0, 4, 12) then re-randomization (1 : 1) to: (n = 64) GUS 50 mg at weeks 16 and 20, then Q8W through week 44 GUS 100 mg at weeks 16 and 20, then Q8W through week 44 GUS 50 mg at weeks 0, 4 and 12, then Q8W through week 44 (n = 65) GUS 100 mg at weeks 0, 4 and 12, then Q8W through week 44 (n = 63) All patients entered a long-term extension from week 52 to 156 at the same dose started at week 20 of double-blind treatment. Once GUS was approved in Japan, only approved GUS dosing regimens and formulations were provided in the study.

Study, phase, identifier (dates)	Treatment groups (number of randomized patients)
X-PLORE, phase II, NCT01483599 (October 2011–August 2013)¹¹	Placebo (weeks 0, 4, 8) → GUS 100 mg at week 16, then Q8W through week 40 (n = 42) GUS 5 mg at weeks 0, 4 and 16, then Q12W through week 40 (n = 41) GUS 15 mg at weeks 0, 8 and 16, then Q8W through week 40 (n = 41) GUS 50 mg at weeks 0, 4 and 16, then Q12W through week 40 (n = 42) GUS 100 mg at weeks 0, 8 and 16, then Q8W through week 40 (n = 42) GUS 200 mg at weeks 0, 4 and 16, then Q12W through week 40 (n = 42) ADA 80 mg at week 0, 40 mg at week 1, then 40 mg Q2W through week 39 (n = 43)
VOYAGE 1, phase III, NCT02207231 (December 2014–June 2020)⁸	Placebo (weeks 0, 4, 12) → GUS 100 mg at weeks 16 and 20, and Q8W through week 252 (n = 174) GUS 100 mg at weeks 0, 4 and 12, and Q8W through week 252 (n = 329) ADA 80 mg at week 0, 40 mg at week 1 and Q2W through week 47 → GUS 100 mg at week 52 and Q8W through week 252 (n = 334)
VOYAGE 2, phase III, NCT02207244 (November 2014–July 2020)⁸	Placebo (weeks 0, 4, 12) → GUS 100 mg at week 16, 20 (n = 248) PASI 90 nonresponders at week 28 continued GUS 100 mg Q8W PASI 90 responders at week 28 were switched to placebo. Upon loss of ≥ 50% of week 28 PASI response or at week 72, patients were retreated with GUS 100 mg, a 100-mg dose 4 weeks later, then Q8W GUS 100 mg at weeks 0, 4, 12 and 20 (n = 496) PASI 90 nonresponders at week 28 continued GUS 100 mg Q8W PASI 90 responders at week 28 were re-randomized 1 : 1 to: GUS 100 mg Q8W Placebo; upon loss of ≥ 50% of week 28 PASI response or at week 72, patients were retreated with GUS 100 mg, a 100-mg dose 4 weeks later, then Q8W ADA 80 mg at week 0, 40 mg at week 1 and Q2W through week 23 (n = 248) PASI 90 nonresponders at week 28 continued GUS 100 mg Q8W PASI 90 responders at week 28 were switched to placebo. Upon loss of ≥ 50% of week 28 PASI response or at week 72, patients were retreated with GUS 100 mg, a 100-mg dose 4 weeks later, then Q8W All patients received open-label GUS 100 mg Q8W from week 76 to 252
NAVIGATE, phase III, NCT02203032 (October 2014–May 2016)¹⁴	All patients received open-label ustekinumab 45 or 90 mg at weeks 0 and 4. IGA was assessed at week 16; scores were used to assign blinded active treatment as follows: IGA ≥ 2: randomized 1 : 1 to: GUS 100 mg at weeks 16 and 20, then Q8W through week 44 (n = 135) Continue ustekinumab Q12W through week 40 (n = 133) IGA 0/1: continue ustekinumab Q12W through week 40 (n = 585)
ORION, phase III, NCT02905331 (March 2017–February 2018)¹⁵	Placebo (weeks 0, 4, 12) → GUS 100 mg (weeks 16, 20, 28) (n = 16) GUS 100 mg (weeks 0, 4, 12, 20, 28); placebo at week 16 to maintain blinding (n = 62)
ECLIPSE, phase III, NCT03090100 (April 2017–September 2018)¹⁶	GUS 100 mg at weeks 0, 4 and 12, then Q8W through week 44 (n = 534) Secukinumab 300 mg at weeks 0, 1, 2, 3 and 4, then Q4W through week 44 (n = 514)
Japan registration, phase III, NCT02325219 (January 2015–February 2019)¹⁷	Placebo (weeks 0, 4, 12) then re-randomization (1 : 1) to: (n = 64) GUS 50 mg at weeks 16 and 20, then Q8W through week 44 GUS 100 mg at weeks 16 and 20, then Q8W through week 44 GUS 50 mg at weeks 0, 4 and 12, then Q8W through week 44 (n = 65) GUS 100 mg at weeks 0, 4 and 12, then Q8W through week 44 (n = 63) All patients entered a long-term extension from week 52 to 156 at the same dose started at week 20 of double-blind treatment. Once GUS was approved in Japan, only approved GUS dosing regimens and formulations were provided in the study.

GUS, guselkumab; ADA, adalimumab; PASI 90, 90% improvement in Psoriasis Area and Severity Index; PASI, Psoriasis Area and Severity Index; IGA, Investigator’s Global Assessment.

Table 1

Overview of randomized controlled trials of psoriasis included in integrated guselkumab safety analyses

Study, phase, identifier (dates)	Treatment groups (number of randomized patients)
X-PLORE, phase II, NCT01483599 (October 2011–August 2013)¹¹	Placebo (weeks 0, 4, 8) → GUS 100 mg at week 16, then Q8W through week 40 (n = 42) GUS 5 mg at weeks 0, 4 and 16, then Q12W through week 40 (n = 41) GUS 15 mg at weeks 0, 8 and 16, then Q8W through week 40 (n = 41) GUS 50 mg at weeks 0, 4 and 16, then Q12W through week 40 (n = 42) GUS 100 mg at weeks 0, 8 and 16, then Q8W through week 40 (n = 42) GUS 200 mg at weeks 0, 4 and 16, then Q12W through week 40 (n = 42) ADA 80 mg at week 0, 40 mg at week 1, then 40 mg Q2W through week 39 (n = 43)
VOYAGE 1, phase III, NCT02207231 (December 2014–June 2020)⁸	Placebo (weeks 0, 4, 12) → GUS 100 mg at weeks 16 and 20, and Q8W through week 252 (n = 174) GUS 100 mg at weeks 0, 4 and 12, and Q8W through week 252 (n = 329) ADA 80 mg at week 0, 40 mg at week 1 and Q2W through week 47 → GUS 100 mg at week 52 and Q8W through week 252 (n = 334)
VOYAGE 2, phase III, NCT02207244 (November 2014–July 2020)⁸	Placebo (weeks 0, 4, 12) → GUS 100 mg at week 16, 20 (n = 248) PASI 90 nonresponders at week 28 continued GUS 100 mg Q8W PASI 90 responders at week 28 were switched to placebo. Upon loss of ≥ 50% of week 28 PASI response or at week 72, patients were retreated with GUS 100 mg, a 100-mg dose 4 weeks later, then Q8W GUS 100 mg at weeks 0, 4, 12 and 20 (n = 496) PASI 90 nonresponders at week 28 continued GUS 100 mg Q8W PASI 90 responders at week 28 were re-randomized 1 : 1 to: GUS 100 mg Q8W Placebo; upon loss of ≥ 50% of week 28 PASI response or at week 72, patients were retreated with GUS 100 mg, a 100-mg dose 4 weeks later, then Q8W ADA 80 mg at week 0, 40 mg at week 1 and Q2W through week 23 (n = 248) PASI 90 nonresponders at week 28 continued GUS 100 mg Q8W PASI 90 responders at week 28 were switched to placebo. Upon loss of ≥ 50% of week 28 PASI response or at week 72, patients were retreated with GUS 100 mg, a 100-mg dose 4 weeks later, then Q8W All patients received open-label GUS 100 mg Q8W from week 76 to 252
NAVIGATE, phase III, NCT02203032 (October 2014–May 2016)¹⁴	All patients received open-label ustekinumab 45 or 90 mg at weeks 0 and 4. IGA was assessed at week 16; scores were used to assign blinded active treatment as follows: IGA ≥ 2: randomized 1 : 1 to: GUS 100 mg at weeks 16 and 20, then Q8W through week 44 (n = 135) Continue ustekinumab Q12W through week 40 (n = 133) IGA 0/1: continue ustekinumab Q12W through week 40 (n = 585)
ORION, phase III, NCT02905331 (March 2017–February 2018)¹⁵	Placebo (weeks 0, 4, 12) → GUS 100 mg (weeks 16, 20, 28) (n = 16) GUS 100 mg (weeks 0, 4, 12, 20, 28); placebo at week 16 to maintain blinding (n = 62)
ECLIPSE, phase III, NCT03090100 (April 2017–September 2018)¹⁶	GUS 100 mg at weeks 0, 4 and 12, then Q8W through week 44 (n = 534) Secukinumab 300 mg at weeks 0, 1, 2, 3 and 4, then Q4W through week 44 (n = 514)
Japan registration, phase III, NCT02325219 (January 2015–February 2019)¹⁷	Placebo (weeks 0, 4, 12) then re-randomization (1 : 1) to: (n = 64) GUS 50 mg at weeks 16 and 20, then Q8W through week 44 GUS 100 mg at weeks 16 and 20, then Q8W through week 44 GUS 50 mg at weeks 0, 4 and 12, then Q8W through week 44 (n = 65) GUS 100 mg at weeks 0, 4 and 12, then Q8W through week 44 (n = 63) All patients entered a long-term extension from week 52 to 156 at the same dose started at week 20 of double-blind treatment. Once GUS was approved in Japan, only approved GUS dosing regimens and formulations were provided in the study.

Study, phase, identifier (dates)	Treatment groups (number of randomized patients)
X-PLORE, phase II, NCT01483599 (October 2011–August 2013)¹¹	Placebo (weeks 0, 4, 8) → GUS 100 mg at week 16, then Q8W through week 40 (n = 42) GUS 5 mg at weeks 0, 4 and 16, then Q12W through week 40 (n = 41) GUS 15 mg at weeks 0, 8 and 16, then Q8W through week 40 (n = 41) GUS 50 mg at weeks 0, 4 and 16, then Q12W through week 40 (n = 42) GUS 100 mg at weeks 0, 8 and 16, then Q8W through week 40 (n = 42) GUS 200 mg at weeks 0, 4 and 16, then Q12W through week 40 (n = 42) ADA 80 mg at week 0, 40 mg at week 1, then 40 mg Q2W through week 39 (n = 43)
VOYAGE 1, phase III, NCT02207231 (December 2014–June 2020)⁸	Placebo (weeks 0, 4, 12) → GUS 100 mg at weeks 16 and 20, and Q8W through week 252 (n = 174) GUS 100 mg at weeks 0, 4 and 12, and Q8W through week 252 (n = 329) ADA 80 mg at week 0, 40 mg at week 1 and Q2W through week 47 → GUS 100 mg at week 52 and Q8W through week 252 (n = 334)
VOYAGE 2, phase III, NCT02207244 (November 2014–July 2020)⁸	Placebo (weeks 0, 4, 12) → GUS 100 mg at week 16, 20 (n = 248) PASI 90 nonresponders at week 28 continued GUS 100 mg Q8W PASI 90 responders at week 28 were switched to placebo. Upon loss of ≥ 50% of week 28 PASI response or at week 72, patients were retreated with GUS 100 mg, a 100-mg dose 4 weeks later, then Q8W GUS 100 mg at weeks 0, 4, 12 and 20 (n = 496) PASI 90 nonresponders at week 28 continued GUS 100 mg Q8W PASI 90 responders at week 28 were re-randomized 1 : 1 to: GUS 100 mg Q8W Placebo; upon loss of ≥ 50% of week 28 PASI response or at week 72, patients were retreated with GUS 100 mg, a 100-mg dose 4 weeks later, then Q8W ADA 80 mg at week 0, 40 mg at week 1 and Q2W through week 23 (n = 248) PASI 90 nonresponders at week 28 continued GUS 100 mg Q8W PASI 90 responders at week 28 were switched to placebo. Upon loss of ≥ 50% of week 28 PASI response or at week 72, patients were retreated with GUS 100 mg, a 100-mg dose 4 weeks later, then Q8W All patients received open-label GUS 100 mg Q8W from week 76 to 252
NAVIGATE, phase III, NCT02203032 (October 2014–May 2016)¹⁴	All patients received open-label ustekinumab 45 or 90 mg at weeks 0 and 4. IGA was assessed at week 16; scores were used to assign blinded active treatment as follows: IGA ≥ 2: randomized 1 : 1 to: GUS 100 mg at weeks 16 and 20, then Q8W through week 44 (n = 135) Continue ustekinumab Q12W through week 40 (n = 133) IGA 0/1: continue ustekinumab Q12W through week 40 (n = 585)
ORION, phase III, NCT02905331 (March 2017–February 2018)¹⁵	Placebo (weeks 0, 4, 12) → GUS 100 mg (weeks 16, 20, 28) (n = 16) GUS 100 mg (weeks 0, 4, 12, 20, 28); placebo at week 16 to maintain blinding (n = 62)
ECLIPSE, phase III, NCT03090100 (April 2017–September 2018)¹⁶	GUS 100 mg at weeks 0, 4 and 12, then Q8W through week 44 (n = 534) Secukinumab 300 mg at weeks 0, 1, 2, 3 and 4, then Q4W through week 44 (n = 514)
Japan registration, phase III, NCT02325219 (January 2015–February 2019)¹⁷	Placebo (weeks 0, 4, 12) then re-randomization (1 : 1) to: (n = 64) GUS 50 mg at weeks 16 and 20, then Q8W through week 44 GUS 100 mg at weeks 16 and 20, then Q8W through week 44 GUS 50 mg at weeks 0, 4 and 12, then Q8W through week 44 (n = 65) GUS 100 mg at weeks 0, 4 and 12, then Q8W through week 44 (n = 63) All patients entered a long-term extension from week 52 to 156 at the same dose started at week 20 of double-blind treatment. Once GUS was approved in Japan, only approved GUS dosing regimens and formulations were provided in the study.

GUS, guselkumab; ADA, adalimumab; PASI 90, 90% improvement in Psoriasis Area and Severity Index; PASI, Psoriasis Area and Severity Index; IGA, Investigator’s Global Assessment.

Detailed eligibility criteria for all studies have been reported previously.^11–17 Patients with stable concomitant medical conditions considered to not interfere with the evaluation of psoriasis or to compromise patient wellbeing were generally eligible to participate if all other inclusion/exclusion criteria were satisfied. Relevant to this safety analysis, patients with stable inflammatory bowel disease (IBD), cardiovascular and metabolic disease, and depression were generally eligible to participate. Patients with a history of suicidality were eligible to participate in X-PLORE, VOYAGE 1, VOYAGE 2, Japan registration, and NAVIGATE, without restriction. In ECLIPSE and ORION, patients with a history of suicidality were eligible unless they had exhibited unstable suicidal ideation or behaviour in the last 6 months and the risk was confirmed by a mental health professional. Patients were also eligible if they had a history of treated nonmelanoma skin cancer (NMSC) or cervical cancer in situ without evidence of recurrence for ≥ 3 months, or a history of other malignancy more than 5 years prior to enrolment. Patients with latent tuberculosis (TB) infection (LTBI) identified during screening were eligible if active TB was ruled out and appropriate LTBI treatment was initiated prior to or simultaneously with the first administration of study agent.

Patients who received prior treatment with guselkumab or with IL-12/23, IL-17, other IL-23, or tumour necrosis factor (TNF)-α inhibitors within 3–6 months (depending on drug class and study) or other systemic immunomodulators (within 4 weeks) of the first study treatment were excluded. For active-comparator studies,^11–14,16 any previous exposure to the active comparator was prohibited. In general, concomitant psoriasis therapies (except topical moisturizers and nonprescription medicated shampoos) were prohibited during study participation. In studies with open-label extensions,^12,13,17 topical therapies, excluding ultra-high-potency corticosteroids, could be used during the open-label periods.

Safety assessments

Short-term safety was evaluated using integrated data from patients randomized and treated with placebo or guselkumab through week 16 in studies with placebo-controlled periods.^{11–13,15,17} Long-term safety was evaluated using data from all patients who received one or more dose of guselkumab, including patients randomized to placebo or adalimumab who crossed over to guselkumab (VOYAGE 1 and 2)^12,13 and patients randomized to guselkumab after receiving open-label ustekinumab (NAVIGATE).¹⁴

Adverse events (AEs) were classified using the Medical Dictionary for Regulatory Activities (MedDRA). AEs of interest included serious infections; opportunistic infections, including TB; Candida infections [assessed in two ways: (i) using the MedDRA high-level term of Candida infections and (ii) based on non-pathogen-specific fungal infections suspicious for Candida (determined by diagnosis and location; MedDRA terms included fungal balanitis, genital fungal infection, vulvovaginal mycotic infection, oral fungal infection, tongue fungal infection, fungal oropharyngitis and fungal oesophagitis)]; malignancies; major adverse cardiovascular events [MACE; cardiovascular death, nonfatal myocardial infarction (MI) and nonfatal stroke]; IBD; suicidal ideation and behaviour; anaphylaxis; and serum-sickness-like reactions.

Statistical analyses

Rates of AEs, AEs leading to study drug discontinuation, serious AEs (SAEs), infections, and other AEs of interest were integrated post hoc, adjusted for the duration of follow-up and reported per 100 PY. An exact method was used to calculate 95% confidence intervals (CIs), assuming that the observed number of events followed a Poisson distribution. Event-level analyses were performed for AEs, SAEs, AEs leading to discontinuation, infections, MACE and IBD. Patient-level analyses were performed for malignancies and suicidal ideation and behaviour. Descriptive analyses were performed for hypersensitivity AEs, including serum-sickness-like and anaphylactic reactions.

Cumulative rates of serious infections, malignancies excluding NMSC [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] and MACE in guselkumab-treated patients in this pooled analysis were compared to rates in patients from the Psoriasis Longitudinal Assessment and Registry (PSOLAR), a disease-based, prospective, real-world observational study that included > 12 000 patients eligible for or receiving conventional systemic and biologic treatments for psoriasis.¹⁸ Comparisons to PSOLAR were performed using data from 2007 to 2014 (> 40 000 PY)^18,19 and 2007 to 2020 (> 74 000 PY).²⁰ Cumulative rates of malignancies other than NMSC were also compared to rates from 2005 to 2011 in a retrospective analysis of patients with psoriasis included in MarketScan^® databases (> 40 000 patients; > 119 000 PY).²¹

Standardized incidence ratios (SIRs) adjusted for age, sex and race were calculated as the number of malignancies other than NMSC and cervical cancer in situ reported in guselkumab-treated patients divided by the expected number of malignancies in the general US population according to the Surveillance, Epidemiology, and End Results (SEER) database (2000–2017).²² Only patients with race identified as White, Black or African American, Asian, American Indian/Alaska Native, Native Hawaiian or Other Pacific Islander were included because these are the categories included in SEER.

Results

Patients

The seven pooled phase II/III studies included 3708 randomized patients. Baseline demographic and disease characteristics were generally similar across studies, although patients in the Japan registration study had a lower mean body mass index (BMI) and higher mean percentage body surface area of psoriasis and Psoriasis Area and Severity Index scores. Baseline medical history across studies showed that roughly half of patients were current/former smokers; common comorbidities included hypertension, hyperlipidaemia, diabetes mellitus and depression (Table 2).

Table 2

Baseline demographic and psoriatic disease characteristics, and medical history for all randomized patients, by study

	Phase II	Phase III
	X-PLORE	VOYAGE 1	VOYAGE 2	Japan Registration	ORION	NAVIGATE	ECLIPSE
Randomized patients (n)	293	837	992	192	78	268	1048
Demographics
Mean (SD) age (years)	44.9 (13.0)	43.7 (12.7)	43.5 (12.2)	48.8 (11.5)	46.0 (13.4)	43.6 (13.6)	45.8 (13.6)
Sex
Male	207 (70.6)	608 (72.6)	692 (69.8)	145 (75.5)	53 (67.9)	183 (68.3)	707 (67.5)
Female	86 (29.4)	229 (27.4)	300 (30.2)	47 (24.5)	25 (32.1)	85 (31.7)	341 (32.5)
Race
White	267 (91.1)	684 (81.7)	814 (82.1)	0	70 (89.7)	208 (77.6)	979 (93.4)
Asian	17 (5.8)	121 (14.5)	136 (13.7)	192 (100)	5 (6.4)	49 (18.3)	30 (2.9)
Black/African American	5 (1.7)	17 (2.0)	19 (1.9)	0	2 (2.6)	6 (2.2)	16 (1.5)
American Indian/Alaska native	1 (0.3)	0	5 (0.5)	0	0	0	4 (0.4)
Native Hawaiian/Other Pacific Islander	2 (0.7)	3 (0.4)	3 (0.3)	0	0	2 (0.7)	3 (0.3)
Other	1 (0.3)	10 (1.2)	10 (1.0)	0	0	1 (0.4)	12 (1.1)
Multiple	0	2 (0.2)	5 (0.5)	0	1 (1.3)	1 (0.4)	4 (0.4)
Not reported	0	0	0	0	0	1 (0.4)	0
Mean (SD) weight (kg)	91.3 (22.0)	89.6 (21.8)	88.7 (20.7)	71.2 (15.2)	94.5 (20.9)	90.8 (24.0)	89.2 (21.6)
Mean (SD) BMI (kg m^–2)	30.6 (6.5)	29.6 (6.5)	29.6 (6.5)	25.4 (4.8)	31.4 (6.7)	30.6 (7.9)	29.9 (6.7)
Psoriasis characteristics
Mean (SD) BSA (%)	25.3 (15.6)	27.9 (16.7)	28.5 (16.5)	36.5 (20.0)	19.8 (8.9)	31.0 (18.8)	24.1 (13.7)
Mean (SD) PASI (0–72)	20.9 (8.3)	21.8 (9.2)	21.8 (8.6)	26.1 (12.0)	18.0 (4.3)	22.7 (9.3)	20.0 (7.5)
IGA score moderate	–	624 (74.6)	766 (77.2)	153 (79.7)	66 (84.6)	203 (75.7)	798 (76.1)
IGA score severe	–	210 (25.1)	225 (22.7)	38 (19.8)	12 (15.4)	65 (24.3)	249 (23.8)
Mean (SD) duration of PsO (years)	18.6 (12.4)	17.5 (11.9)	17.8 (11.9)	14.4 (9.5)	18.7 (12.1)	16.9 (11.9)	18.4 (12.4)
Patients with PsA	75 (25.6)	156 (18.6)	179 (18.0)	31 (16.1)	13 (16.7)	49 (18.3)	176 (16.8)
Prior PsO treatmentsⁱ
Topical agents	283 (96.6)	762 (91.1)	947 (95.6)	191 (99.5)	74 (94.9)	254 (94.8)	989 (94.6)
Phototherapy (PUVA or UVB)	154 (52.6)	454 (54.3)	565 (57.0)	96 (50.0)	40 (51.3)	144 (53.7)	542 (51.8)
Nonbiologic systemic drugs	147 (50.2)^a	517 (61.8)^b	639 (64.4)^b	115 (59.9)^b	36 (46.2)^b	153 (57.1)^b	563 (53.7)^b
Biologics	126 (43.0)^c	175 (20.9)^d	204 (20.6)^d	35 (18.2)^e	45 (57.7)^e	60 (22.4)^f	305 (29.1)^g
Medical history
Hypertension	79 (27.0)	203 (24.3)	269 (27.1)	78 (40.6)	30 (38.5)	78 (29.1)	301 (28.7)
Hyperlipidaemia	56 (19.1)	120 (14.3)	141 (14.2)	51 (26.6)	20 (25.6)	48 (17.9)	188 (17.9)
Diabetes mellitus	27 (9.2)	68 (8.1)	93 (9.4)	28 (14.6)	14 (17.9)	19 (7.1)	136 (13.0)
CAD	5 (1.7)	19 (2.3)	23 (2.3)	0	3 (3.8)	6 (2.2)	37 (3.5)
MI	4 (1.4)	12 (1.4)	13 (1.3)	0	0	5 (1.9)	12 (1.1)
CABG	1 (0.3)	1 (0.1)	7 (0.7)	0	0	1 (0.4)	11 (1.0)
PCI	2 (0.7)	6 (0.7)	8 (0.8)	0	0	1 (0.4)	14 (1.3)
Family history of early CAD (< 55 years)	20 (6.8)	57 (6.8)	75 (7.6)	3 (1.6)	9 (11.5)	24 (9.0)	101 (9.6)
Stroke	1 (0.3)	4 (0.5)	2 (0.2)	1 (0.5)	0	0	7 (0.7)
TIA	3 (1.0)	2 (0.2)	2 (0.2)	0	0	0	7 (0.7)
Current or former smoker	161 (54.9)	433 (51.7)	505 (50.9)	147 (76.6)	33 (42.3)	132 (49.3)	602 (57.4)
Depression	24 (8.2)	64 (7.6)	76 (7.7)	2 (1.0)	7 (9.0)	25 (9.3)	100 (9.5)
Skin SCC	3 (1.0)	1 (0.1)	0	1 (0.5)	0	2 (0.7)	11 (1.0)
Skin BCC	5 (1.7)	8 (1.0)	6 (0.6)	0	0	2 (0.7)	11 (1.0)
Other malignancies	–	9 (1.1)	11 (1.1)	–	1 (1.3)	0	12 (1.1)
Family history of first-degree relative carcinoma^h	52 (17.7)	144 (17.2)	174 (17.5)	47 (24.5)	20 (25.6)	48 (17.9)	253 (24.1)

	Phase II	Phase III
	X-PLORE	VOYAGE 1	VOYAGE 2	Japan Registration	ORION	NAVIGATE	ECLIPSE
Randomized patients (n)	293	837	992	192	78	268	1048
Demographics
Mean (SD) age (years)	44.9 (13.0)	43.7 (12.7)	43.5 (12.2)	48.8 (11.5)	46.0 (13.4)	43.6 (13.6)	45.8 (13.6)
Sex
Male	207 (70.6)	608 (72.6)	692 (69.8)	145 (75.5)	53 (67.9)	183 (68.3)	707 (67.5)
Female	86 (29.4)	229 (27.4)	300 (30.2)	47 (24.5)	25 (32.1)	85 (31.7)	341 (32.5)
Race
White	267 (91.1)	684 (81.7)	814 (82.1)	0	70 (89.7)	208 (77.6)	979 (93.4)
Asian	17 (5.8)	121 (14.5)	136 (13.7)	192 (100)	5 (6.4)	49 (18.3)	30 (2.9)
Black/African American	5 (1.7)	17 (2.0)	19 (1.9)	0	2 (2.6)	6 (2.2)	16 (1.5)
American Indian/Alaska native	1 (0.3)	0	5 (0.5)	0	0	0	4 (0.4)
Native Hawaiian/Other Pacific Islander	2 (0.7)	3 (0.4)	3 (0.3)	0	0	2 (0.7)	3 (0.3)
Other	1 (0.3)	10 (1.2)	10 (1.0)	0	0	1 (0.4)	12 (1.1)
Multiple	0	2 (0.2)	5 (0.5)	0	1 (1.3)	1 (0.4)	4 (0.4)
Not reported	0	0	0	0	0	1 (0.4)	0
Mean (SD) weight (kg)	91.3 (22.0)	89.6 (21.8)	88.7 (20.7)	71.2 (15.2)	94.5 (20.9)	90.8 (24.0)	89.2 (21.6)
Mean (SD) BMI (kg m^–2)	30.6 (6.5)	29.6 (6.5)	29.6 (6.5)	25.4 (4.8)	31.4 (6.7)	30.6 (7.9)	29.9 (6.7)
Psoriasis characteristics
Mean (SD) BSA (%)	25.3 (15.6)	27.9 (16.7)	28.5 (16.5)	36.5 (20.0)	19.8 (8.9)	31.0 (18.8)	24.1 (13.7)
Mean (SD) PASI (0–72)	20.9 (8.3)	21.8 (9.2)	21.8 (8.6)	26.1 (12.0)	18.0 (4.3)	22.7 (9.3)	20.0 (7.5)
IGA score moderate	–	624 (74.6)	766 (77.2)	153 (79.7)	66 (84.6)	203 (75.7)	798 (76.1)
IGA score severe	–	210 (25.1)	225 (22.7)	38 (19.8)	12 (15.4)	65 (24.3)	249 (23.8)
Mean (SD) duration of PsO (years)	18.6 (12.4)	17.5 (11.9)	17.8 (11.9)	14.4 (9.5)	18.7 (12.1)	16.9 (11.9)	18.4 (12.4)
Patients with PsA	75 (25.6)	156 (18.6)	179 (18.0)	31 (16.1)	13 (16.7)	49 (18.3)	176 (16.8)
Prior PsO treatmentsⁱ
Topical agents	283 (96.6)	762 (91.1)	947 (95.6)	191 (99.5)	74 (94.9)	254 (94.8)	989 (94.6)
Phototherapy (PUVA or UVB)	154 (52.6)	454 (54.3)	565 (57.0)	96 (50.0)	40 (51.3)	144 (53.7)	542 (51.8)
Nonbiologic systemic drugs	147 (50.2)^a	517 (61.8)^b	639 (64.4)^b	115 (59.9)^b	36 (46.2)^b	153 (57.1)^b	563 (53.7)^b
Biologics	126 (43.0)^c	175 (20.9)^d	204 (20.6)^d	35 (18.2)^e	45 (57.7)^e	60 (22.4)^f	305 (29.1)^g
Medical history
Hypertension	79 (27.0)	203 (24.3)	269 (27.1)	78 (40.6)	30 (38.5)	78 (29.1)	301 (28.7)
Hyperlipidaemia	56 (19.1)	120 (14.3)	141 (14.2)	51 (26.6)	20 (25.6)	48 (17.9)	188 (17.9)
Diabetes mellitus	27 (9.2)	68 (8.1)	93 (9.4)	28 (14.6)	14 (17.9)	19 (7.1)	136 (13.0)
CAD	5 (1.7)	19 (2.3)	23 (2.3)	0	3 (3.8)	6 (2.2)	37 (3.5)
MI	4 (1.4)	12 (1.4)	13 (1.3)	0	0	5 (1.9)	12 (1.1)
CABG	1 (0.3)	1 (0.1)	7 (0.7)	0	0	1 (0.4)	11 (1.0)
PCI	2 (0.7)	6 (0.7)	8 (0.8)	0	0	1 (0.4)	14 (1.3)
Family history of early CAD (< 55 years)	20 (6.8)	57 (6.8)	75 (7.6)	3 (1.6)	9 (11.5)	24 (9.0)	101 (9.6)
Stroke	1 (0.3)	4 (0.5)	2 (0.2)	1 (0.5)	0	0	7 (0.7)
TIA	3 (1.0)	2 (0.2)	2 (0.2)	0	0	0	7 (0.7)
Current or former smoker	161 (54.9)	433 (51.7)	505 (50.9)	147 (76.6)	33 (42.3)	132 (49.3)	602 (57.4)
Depression	24 (8.2)	64 (7.6)	76 (7.7)	2 (1.0)	7 (9.0)	25 (9.3)	100 (9.5)
Skin SCC	3 (1.0)	1 (0.1)	0	1 (0.5)	0	2 (0.7)	11 (1.0)
Skin BCC	5 (1.7)	8 (1.0)	6 (0.6)	0	0	2 (0.7)	11 (1.0)
Other malignancies	–	9 (1.1)	11 (1.1)	–	1 (1.3)	0	12 (1.1)
Family history of first-degree relative carcinoma^h	52 (17.7)	144 (17.2)	174 (17.5)	47 (24.5)	20 (25.6)	48 (17.9)	253 (24.1)

Data are presented as n (%) unless otherwise stated. BMI, body mass index; BSA, body surface area; PASI, Psoriasis Area and Severity Index; IGA, Investigator’s Global Assessment; PsO, psoriasis; PsA, psoriatic arthritis; PUVA, psoralen + ultraviolet A; UVB, ultraviolet B; CAD, coronary artery disease; MI, myocardial infarction; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; TIA, transient ischaemic attack; SCC, squamous cell carcinoma; BCC, basal cell carcinoma. ^aIncludes PUVA, methotrexate, acitretin or ciclosporin. ^bIncludes PUVA, methotrexate, ciclosporin, acitretin, apremilast or tofacitinib. ^cIncludes ustekinumab, etanercept, infliximab, efalizumab, alefacept or briakinumab. ^dIncludes etanercept, infliximab, alefacept, efalizumab, ustekinumab, briakinumab, secukinumab, ixekizumab or brodalumab. ^eIncludes etanercept, infliximab, efalizumab, alefacept, brodalumab, ixekizumab, secukinumab, briakinumab, adalimumab or ustekinumab. ^fIncludes etanercept, infliximab, adalimumab, alefacept, efalizumab, brodalumab, secukinumab, ixekizumab or briakinumab. ^gIncludes etanercept, infliximab, alefacept, efalizumab, ustekinumab, briakinumab, ixekizumab, adalimumab, brodalumab, tildrakizumab or risankizumab. ^hExcluding skin SCC and skin BCC. ⁱDue to missing baseline values, the denominators to calculate the percentages may not always include all patients randomized at baseline.

Table 2

Baseline demographic and psoriatic disease characteristics, and medical history for all randomized patients, by study

	Phase II	Phase III
	X-PLORE	VOYAGE 1	VOYAGE 2	Japan Registration	ORION	NAVIGATE	ECLIPSE
Randomized patients (n)	293	837	992	192	78	268	1048
Demographics
Mean (SD) age (years)	44.9 (13.0)	43.7 (12.7)	43.5 (12.2)	48.8 (11.5)	46.0 (13.4)	43.6 (13.6)	45.8 (13.6)
Sex
Male	207 (70.6)	608 (72.6)	692 (69.8)	145 (75.5)	53 (67.9)	183 (68.3)	707 (67.5)
Female	86 (29.4)	229 (27.4)	300 (30.2)	47 (24.5)	25 (32.1)	85 (31.7)	341 (32.5)
Race
White	267 (91.1)	684 (81.7)	814 (82.1)	0	70 (89.7)	208 (77.6)	979 (93.4)
Asian	17 (5.8)	121 (14.5)	136 (13.7)	192 (100)	5 (6.4)	49 (18.3)	30 (2.9)
Black/African American	5 (1.7)	17 (2.0)	19 (1.9)	0	2 (2.6)	6 (2.2)	16 (1.5)
American Indian/Alaska native	1 (0.3)	0	5 (0.5)	0	0	0	4 (0.4)
Native Hawaiian/Other Pacific Islander	2 (0.7)	3 (0.4)	3 (0.3)	0	0	2 (0.7)	3 (0.3)
Other	1 (0.3)	10 (1.2)	10 (1.0)	0	0	1 (0.4)	12 (1.1)
Multiple	0	2 (0.2)	5 (0.5)	0	1 (1.3)	1 (0.4)	4 (0.4)
Not reported	0	0	0	0	0	1 (0.4)	0
Mean (SD) weight (kg)	91.3 (22.0)	89.6 (21.8)	88.7 (20.7)	71.2 (15.2)	94.5 (20.9)	90.8 (24.0)	89.2 (21.6)
Mean (SD) BMI (kg m^–2)	30.6 (6.5)	29.6 (6.5)	29.6 (6.5)	25.4 (4.8)	31.4 (6.7)	30.6 (7.9)	29.9 (6.7)
Psoriasis characteristics
Mean (SD) BSA (%)	25.3 (15.6)	27.9 (16.7)	28.5 (16.5)	36.5 (20.0)	19.8 (8.9)	31.0 (18.8)	24.1 (13.7)
Mean (SD) PASI (0–72)	20.9 (8.3)	21.8 (9.2)	21.8 (8.6)	26.1 (12.0)	18.0 (4.3)	22.7 (9.3)	20.0 (7.5)
IGA score moderate	–	624 (74.6)	766 (77.2)	153 (79.7)	66 (84.6)	203 (75.7)	798 (76.1)
IGA score severe	–	210 (25.1)	225 (22.7)	38 (19.8)	12 (15.4)	65 (24.3)	249 (23.8)
Mean (SD) duration of PsO (years)	18.6 (12.4)	17.5 (11.9)	17.8 (11.9)	14.4 (9.5)	18.7 (12.1)	16.9 (11.9)	18.4 (12.4)
Patients with PsA	75 (25.6)	156 (18.6)	179 (18.0)	31 (16.1)	13 (16.7)	49 (18.3)	176 (16.8)
Prior PsO treatmentsⁱ
Topical agents	283 (96.6)	762 (91.1)	947 (95.6)	191 (99.5)	74 (94.9)	254 (94.8)	989 (94.6)
Phototherapy (PUVA or UVB)	154 (52.6)	454 (54.3)	565 (57.0)	96 (50.0)	40 (51.3)	144 (53.7)	542 (51.8)
Nonbiologic systemic drugs	147 (50.2)^a	517 (61.8)^b	639 (64.4)^b	115 (59.9)^b	36 (46.2)^b	153 (57.1)^b	563 (53.7)^b
Biologics	126 (43.0)^c	175 (20.9)^d	204 (20.6)^d	35 (18.2)^e	45 (57.7)^e	60 (22.4)^f	305 (29.1)^g
Medical history
Hypertension	79 (27.0)	203 (24.3)	269 (27.1)	78 (40.6)	30 (38.5)	78 (29.1)	301 (28.7)
Hyperlipidaemia	56 (19.1)	120 (14.3)	141 (14.2)	51 (26.6)	20 (25.6)	48 (17.9)	188 (17.9)
Diabetes mellitus	27 (9.2)	68 (8.1)	93 (9.4)	28 (14.6)	14 (17.9)	19 (7.1)	136 (13.0)
CAD	5 (1.7)	19 (2.3)	23 (2.3)	0	3 (3.8)	6 (2.2)	37 (3.5)
MI	4 (1.4)	12 (1.4)	13 (1.3)	0	0	5 (1.9)	12 (1.1)
CABG	1 (0.3)	1 (0.1)	7 (0.7)	0	0	1 (0.4)	11 (1.0)
PCI	2 (0.7)	6 (0.7)	8 (0.8)	0	0	1 (0.4)	14 (1.3)
Family history of early CAD (< 55 years)	20 (6.8)	57 (6.8)	75 (7.6)	3 (1.6)	9 (11.5)	24 (9.0)	101 (9.6)
Stroke	1 (0.3)	4 (0.5)	2 (0.2)	1 (0.5)	0	0	7 (0.7)
TIA	3 (1.0)	2 (0.2)	2 (0.2)	0	0	0	7 (0.7)
Current or former smoker	161 (54.9)	433 (51.7)	505 (50.9)	147 (76.6)	33 (42.3)	132 (49.3)	602 (57.4)
Depression	24 (8.2)	64 (7.6)	76 (7.7)	2 (1.0)	7 (9.0)	25 (9.3)	100 (9.5)
Skin SCC	3 (1.0)	1 (0.1)	0	1 (0.5)	0	2 (0.7)	11 (1.0)
Skin BCC	5 (1.7)	8 (1.0)	6 (0.6)	0	0	2 (0.7)	11 (1.0)
Other malignancies	–	9 (1.1)	11 (1.1)	–	1 (1.3)	0	12 (1.1)
Family history of first-degree relative carcinoma^h	52 (17.7)	144 (17.2)	174 (17.5)	47 (24.5)	20 (25.6)	48 (17.9)	253 (24.1)

	Phase II	Phase III
	X-PLORE	VOYAGE 1	VOYAGE 2	Japan Registration	ORION	NAVIGATE	ECLIPSE
Randomized patients (n)	293	837	992	192	78	268	1048
Demographics
Mean (SD) age (years)	44.9 (13.0)	43.7 (12.7)	43.5 (12.2)	48.8 (11.5)	46.0 (13.4)	43.6 (13.6)	45.8 (13.6)
Sex
Male	207 (70.6)	608 (72.6)	692 (69.8)	145 (75.5)	53 (67.9)	183 (68.3)	707 (67.5)
Female	86 (29.4)	229 (27.4)	300 (30.2)	47 (24.5)	25 (32.1)	85 (31.7)	341 (32.5)
Race
White	267 (91.1)	684 (81.7)	814 (82.1)	0	70 (89.7)	208 (77.6)	979 (93.4)
Asian	17 (5.8)	121 (14.5)	136 (13.7)	192 (100)	5 (6.4)	49 (18.3)	30 (2.9)
Black/African American	5 (1.7)	17 (2.0)	19 (1.9)	0	2 (2.6)	6 (2.2)	16 (1.5)
American Indian/Alaska native	1 (0.3)	0	5 (0.5)	0	0	0	4 (0.4)
Native Hawaiian/Other Pacific Islander	2 (0.7)	3 (0.4)	3 (0.3)	0	0	2 (0.7)	3 (0.3)
Other	1 (0.3)	10 (1.2)	10 (1.0)	0	0	1 (0.4)	12 (1.1)
Multiple	0	2 (0.2)	5 (0.5)	0	1 (1.3)	1 (0.4)	4 (0.4)
Not reported	0	0	0	0	0	1 (0.4)	0
Mean (SD) weight (kg)	91.3 (22.0)	89.6 (21.8)	88.7 (20.7)	71.2 (15.2)	94.5 (20.9)	90.8 (24.0)	89.2 (21.6)
Mean (SD) BMI (kg m^–2)	30.6 (6.5)	29.6 (6.5)	29.6 (6.5)	25.4 (4.8)	31.4 (6.7)	30.6 (7.9)	29.9 (6.7)
Psoriasis characteristics
Mean (SD) BSA (%)	25.3 (15.6)	27.9 (16.7)	28.5 (16.5)	36.5 (20.0)	19.8 (8.9)	31.0 (18.8)	24.1 (13.7)
Mean (SD) PASI (0–72)	20.9 (8.3)	21.8 (9.2)	21.8 (8.6)	26.1 (12.0)	18.0 (4.3)	22.7 (9.3)	20.0 (7.5)
IGA score moderate	–	624 (74.6)	766 (77.2)	153 (79.7)	66 (84.6)	203 (75.7)	798 (76.1)
IGA score severe	–	210 (25.1)	225 (22.7)	38 (19.8)	12 (15.4)	65 (24.3)	249 (23.8)
Mean (SD) duration of PsO (years)	18.6 (12.4)	17.5 (11.9)	17.8 (11.9)	14.4 (9.5)	18.7 (12.1)	16.9 (11.9)	18.4 (12.4)
Patients with PsA	75 (25.6)	156 (18.6)	179 (18.0)	31 (16.1)	13 (16.7)	49 (18.3)	176 (16.8)
Prior PsO treatmentsⁱ
Topical agents	283 (96.6)	762 (91.1)	947 (95.6)	191 (99.5)	74 (94.9)	254 (94.8)	989 (94.6)
Phototherapy (PUVA or UVB)	154 (52.6)	454 (54.3)	565 (57.0)	96 (50.0)	40 (51.3)	144 (53.7)	542 (51.8)
Nonbiologic systemic drugs	147 (50.2)^a	517 (61.8)^b	639 (64.4)^b	115 (59.9)^b	36 (46.2)^b	153 (57.1)^b	563 (53.7)^b
Biologics	126 (43.0)^c	175 (20.9)^d	204 (20.6)^d	35 (18.2)^e	45 (57.7)^e	60 (22.4)^f	305 (29.1)^g
Medical history
Hypertension	79 (27.0)	203 (24.3)	269 (27.1)	78 (40.6)	30 (38.5)	78 (29.1)	301 (28.7)
Hyperlipidaemia	56 (19.1)	120 (14.3)	141 (14.2)	51 (26.6)	20 (25.6)	48 (17.9)	188 (17.9)
Diabetes mellitus	27 (9.2)	68 (8.1)	93 (9.4)	28 (14.6)	14 (17.9)	19 (7.1)	136 (13.0)
CAD	5 (1.7)	19 (2.3)	23 (2.3)	0	3 (3.8)	6 (2.2)	37 (3.5)
MI	4 (1.4)	12 (1.4)	13 (1.3)	0	0	5 (1.9)	12 (1.1)
CABG	1 (0.3)	1 (0.1)	7 (0.7)	0	0	1 (0.4)	11 (1.0)
PCI	2 (0.7)	6 (0.7)	8 (0.8)	0	0	1 (0.4)	14 (1.3)
Family history of early CAD (< 55 years)	20 (6.8)	57 (6.8)	75 (7.6)	3 (1.6)	9 (11.5)	24 (9.0)	101 (9.6)
Stroke	1 (0.3)	4 (0.5)	2 (0.2)	1 (0.5)	0	0	7 (0.7)
TIA	3 (1.0)	2 (0.2)	2 (0.2)	0	0	0	7 (0.7)
Current or former smoker	161 (54.9)	433 (51.7)	505 (50.9)	147 (76.6)	33 (42.3)	132 (49.3)	602 (57.4)
Depression	24 (8.2)	64 (7.6)	76 (7.7)	2 (1.0)	7 (9.0)	25 (9.3)	100 (9.5)
Skin SCC	3 (1.0)	1 (0.1)	0	1 (0.5)	0	2 (0.7)	11 (1.0)
Skin BCC	5 (1.7)	8 (1.0)	6 (0.6)	0	0	2 (0.7)	11 (1.0)
Other malignancies	–	9 (1.1)	11 (1.1)	–	1 (1.3)	0	12 (1.1)
Family history of first-degree relative carcinoma^h	52 (17.7)	144 (17.2)	174 (17.5)	47 (24.5)	20 (25.6)	48 (17.9)	253 (24.1)

During the 16-week placebo-controlled period, 544 patients received placebo (165 PY) and 1220 received guselkumab (378 PY). Over the long-term reporting period, 2891 patients received guselkumab (8662 PY; median exposure 3.5 years). Pooled baseline characteristics across studies were similar for treatment groups in both reporting periods (Table 3). Patients were predominantly male, White, younger than 65 years of age, and overweight or obese. Most patients had not received prior biologics or methotrexate.

Table 3

Pooled baseline demographic characteristics for placebo- and guselkumab-treated patients included in safety analyses

	Patients included in placebo-controlled period (week 0–16) analysis		Patients included in analysis through end of reporting period (up to 5 years)
Characteristic	Placebo (n = 544)	Guselkumab (n = 1220)	Guselkumab (n = 2891)
Age (years)
Mean (SD)	44.6 (12.5)	44.5 (12.6)	44.5 (12.8)
< 65	518 (95.2)	1148 (94.1)	2708 (93.7)
≥ 65	26 (4.8)	72 (5.9)	183 (6.3)
Sex
Male	386 (71.0)	869 (71.2)	2042 (70.6)
Female	158 (29.0)	351 (28.8)	849 (29.4)
Race
White	403 (74.1)	913 (74.8)	2313 (80.0)
Asian	118 (21.7)	266 (21.8)	480 (16.6)
Black/African American	13 (2.4)	16 (1.3)	47 (1.6)
Native Hawaiian/Other Pacific Islander	2 (0.4)	4 (0.3)	7 (0.2)
American Indian/Alaska Native	1 (0.2)	3 (0.2)	6 (0.2)
Other	5 (0.9)	13 (1.1)	27 (0.9)
Multiple	2 (0.4)	5 (0.4)	11 (0.4)
BMI (kg m^–2)^a
Mean (SD)	29.1 (6.7)	29.4 (6.4)	29.5 (6.6)
< 25	158 (29.1)	311 (25.5)	747 (25.9)
25 to < 30 (overweight)	188 (34.6)	422 (34.6)	993 (34.4)
≥ 30 (obese)	197 (36.3)	487 (39.9)	1148 (39.8)
Prior biologic treatment
Yes	121 (22.2)	319 (26.1)	712 (24.6)
No	423 (77.8)	901 (73.9)	2179 (75.4)
Prior methotrexate treatment
Yes	173 (31.8)	462 (37.9)	1073 (37.1)
No	371 (68.2)	758 (62.1)	1818 (62.9)

	Patients included in placebo-controlled period (week 0–16) analysis		Patients included in analysis through end of reporting period (up to 5 years)
Characteristic	Placebo (n = 544)	Guselkumab (n = 1220)	Guselkumab (n = 2891)
Age (years)
Mean (SD)	44.6 (12.5)	44.5 (12.6)	44.5 (12.8)
< 65	518 (95.2)	1148 (94.1)	2708 (93.7)
≥ 65	26 (4.8)	72 (5.9)	183 (6.3)
Sex
Male	386 (71.0)	869 (71.2)	2042 (70.6)
Female	158 (29.0)	351 (28.8)	849 (29.4)
Race
White	403 (74.1)	913 (74.8)	2313 (80.0)
Asian	118 (21.7)	266 (21.8)	480 (16.6)
Black/African American	13 (2.4)	16 (1.3)	47 (1.6)
Native Hawaiian/Other Pacific Islander	2 (0.4)	4 (0.3)	7 (0.2)
American Indian/Alaska Native	1 (0.2)	3 (0.2)	6 (0.2)
Other	5 (0.9)	13 (1.1)	27 (0.9)
Multiple	2 (0.4)	5 (0.4)	11 (0.4)
BMI (kg m^–2)^a
Mean (SD)	29.1 (6.7)	29.4 (6.4)	29.5 (6.6)
< 25	158 (29.1)	311 (25.5)	747 (25.9)
25 to < 30 (overweight)	188 (34.6)	422 (34.6)	993 (34.4)
≥ 30 (obese)	197 (36.3)	487 (39.9)	1148 (39.8)
Prior biologic treatment
Yes	121 (22.2)	319 (26.1)	712 (24.6)
No	423 (77.8)	901 (73.9)	2179 (75.4)
Prior methotrexate treatment
Yes	173 (31.8)	462 (37.9)	1073 (37.1)
No	371 (68.2)	758 (62.1)	1818 (62.9)

Data are presented as n (%) unless otherwise indicated. BMI, body mass index. ^aPlacebo, n = 543; guselkumab through end of reporting period, n = 2888.

Table 3

Pooled baseline demographic characteristics for placebo- and guselkumab-treated patients included in safety analyses

	Patients included in placebo-controlled period (week 0–16) analysis		Patients included in analysis through end of reporting period (up to 5 years)
Characteristic	Placebo (n = 544)	Guselkumab (n = 1220)	Guselkumab (n = 2891)
Age (years)
Mean (SD)	44.6 (12.5)	44.5 (12.6)	44.5 (12.8)
< 65	518 (95.2)	1148 (94.1)	2708 (93.7)
≥ 65	26 (4.8)	72 (5.9)	183 (6.3)
Sex
Male	386 (71.0)	869 (71.2)	2042 (70.6)
Female	158 (29.0)	351 (28.8)	849 (29.4)
Race
White	403 (74.1)	913 (74.8)	2313 (80.0)
Asian	118 (21.7)	266 (21.8)	480 (16.6)
Black/African American	13 (2.4)	16 (1.3)	47 (1.6)
Native Hawaiian/Other Pacific Islander	2 (0.4)	4 (0.3)	7 (0.2)
American Indian/Alaska Native	1 (0.2)	3 (0.2)	6 (0.2)
Other	5 (0.9)	13 (1.1)	27 (0.9)
Multiple	2 (0.4)	5 (0.4)	11 (0.4)
BMI (kg m^–2)^a
Mean (SD)	29.1 (6.7)	29.4 (6.4)	29.5 (6.6)
< 25	158 (29.1)	311 (25.5)	747 (25.9)
25 to < 30 (overweight)	188 (34.6)	422 (34.6)	993 (34.4)
≥ 30 (obese)	197 (36.3)	487 (39.9)	1148 (39.8)
Prior biologic treatment
Yes	121 (22.2)	319 (26.1)	712 (24.6)
No	423 (77.8)	901 (73.9)	2179 (75.4)
Prior methotrexate treatment
Yes	173 (31.8)	462 (37.9)	1073 (37.1)
No	371 (68.2)	758 (62.1)	1818 (62.9)

	Patients included in placebo-controlled period (week 0–16) analysis		Patients included in analysis through end of reporting period (up to 5 years)
Characteristic	Placebo (n = 544)	Guselkumab (n = 1220)	Guselkumab (n = 2891)
Age (years)
Mean (SD)	44.6 (12.5)	44.5 (12.6)	44.5 (12.8)
< 65	518 (95.2)	1148 (94.1)	2708 (93.7)
≥ 65	26 (4.8)	72 (5.9)	183 (6.3)
Sex
Male	386 (71.0)	869 (71.2)	2042 (70.6)
Female	158 (29.0)	351 (28.8)	849 (29.4)
Race
White	403 (74.1)	913 (74.8)	2313 (80.0)
Asian	118 (21.7)	266 (21.8)	480 (16.6)
Black/African American	13 (2.4)	16 (1.3)	47 (1.6)
Native Hawaiian/Other Pacific Islander	2 (0.4)	4 (0.3)	7 (0.2)
American Indian/Alaska Native	1 (0.2)	3 (0.2)	6 (0.2)
Other	5 (0.9)	13 (1.1)	27 (0.9)
Multiple	2 (0.4)	5 (0.4)	11 (0.4)
BMI (kg m^–2)^a
Mean (SD)	29.1 (6.7)	29.4 (6.4)	29.5 (6.6)
< 25	158 (29.1)	311 (25.5)	747 (25.9)
25 to < 30 (overweight)	188 (34.6)	422 (34.6)	993 (34.4)
≥ 30 (obese)	197 (36.3)	487 (39.9)	1148 (39.8)
Prior biologic treatment
Yes	121 (22.2)	319 (26.1)	712 (24.6)
No	423 (77.8)	901 (73.9)	2179 (75.4)
Prior methotrexate treatment
Yes	173 (31.8)	462 (37.9)	1073 (37.1)
No	371 (68.2)	758 (62.1)	1818 (62.9)

Data are presented as n (%) unless otherwise indicated. BMI, body mass index. ^aPlacebo, n = 543; guselkumab through end of reporting period, n = 2888.

Adverse events

During the placebo-controlled period, exposure-adjusted incidence rates (EAIRs) of AEs were similar between guselkumab- and placebo-treated patients [346/100 PY (95% CI 327–365) vs. 341/100 PY (95% CI 314–371)] and did not increase in guselkumab-treated patients over the long-term reporting period (169/100 PY, 95% CI 166–172) (Table 4). EAIRs of SAEs were low and similar for the guselkumab and placebo groups through week 16 [6.34/100 PY (95% CI 4.06–9.44) vs. 6.66/100 PY (95% CI 3.33–11.93)] and remained low and comparable with guselkumab treatment for up to 5 years (5.26/100 PY, 95% CI 4.79–5.77). The EAIR of AEs leading to discontinuation was lower with guselkumab vs. placebo through week 16 [5.02/100 PY (95% CI 3.02–7.84) vs. 9.69/100 PY (95% CI 5.54–15.74)], although 95% CIs were wide and overlapping. The EAIR of AEs leading to discontinuation remained low in guselkumab-treated patients over the long-term reporting period (1.59/100 PY, 95% CI 1.34–1.88) (Table 4).

Table 4

Exposure-adjusted rates of events per 100 person-years (PY) of follow-up during the placebo-controlled period and through the end of the reporting period

	Placebo-controlled period		Through end of reporting period
	Placebo (95% CI)	Guselkumab (95% CI)	Guselkumab (95% CI)^a
Patients treated, n	544	1220	2891
Total PY of follow-up	165	378	8662
Median PY of follow-up	0.3	0.3	3.5
≥ 1 AE	341 (314–371)	346 (327–365)	169 (166–172)
AEs leading to discontinuation	9.69 (5.54–15.74)	5.02 (3.02–7.84)	1.59 (1.34–1.88)
≥ 1 SAE	6.66 (3.33–11.93)	6.34 (4.06–9.44)	5.26 (4.79–5.77)
Infections	83.61 (70.25–98.79)	95.92 (86.31–106.31)	65.92 (64.22–67.65)
Candida infections	1.82 (0.37–5.31)	0.53 (0.06–1.91)	0.60 (0.45–0.79)
Non-pathogen-specific fungal infections suspicious for Candida	0 (0.00–1.82)	0.53 (0.06–1.91)	0.10 (0.05–0.20)
Serious infections	1.21 (0.15–4.38)	1.06 (0.29–2.71)	0.88 (0.69–1.10)
Malignancy^b	0 (0.00–1.82)	0.53 (0.06–1.91)	0.74 (0.57–0.95)
NMSC	0 (0.00–1.82)	0.26 (0.01–1.47)	0.35 (0.23–0.50)
Other malignancies	0 (0.00–1.82)	0.26 (0.01–1.47)	0.43 (0.30–0.59)
MACE^c	0 (0.00–1.82)	0.26 (0.01–1.47)	0.33 (0.22–0.48)
IBD	0 (0.00–1.82)	0 (0.00–0.79)	0 (0.00–0.03)
Crohn disease/ulcerative colitis	0 (0.00–1.82)	0 (0.00–0.79)	0 (0.00–0.03)
Suicidal ideation and behaviour^b	0 (0.00–1.82)	0 (0.00–0.79)	0.10 (0.05–0.20)

	Placebo-controlled period		Through end of reporting period
	Placebo (95% CI)	Guselkumab (95% CI)	Guselkumab (95% CI)^a
Patients treated, n	544	1220	2891
Total PY of follow-up	165	378	8662
Median PY of follow-up	0.3	0.3	3.5
≥ 1 AE	341 (314–371)	346 (327–365)	169 (166–172)
AEs leading to discontinuation	9.69 (5.54–15.74)	5.02 (3.02–7.84)	1.59 (1.34–1.88)
≥ 1 SAE	6.66 (3.33–11.93)	6.34 (4.06–9.44)	5.26 (4.79–5.77)
Infections	83.61 (70.25–98.79)	95.92 (86.31–106.31)	65.92 (64.22–67.65)
Candida infections	1.82 (0.37–5.31)	0.53 (0.06–1.91)	0.60 (0.45–0.79)
Non-pathogen-specific fungal infections suspicious for Candida	0 (0.00–1.82)	0.53 (0.06–1.91)	0.10 (0.05–0.20)
Serious infections	1.21 (0.15–4.38)	1.06 (0.29–2.71)	0.88 (0.69–1.10)
Malignancy^b	0 (0.00–1.82)	0.53 (0.06–1.91)	0.74 (0.57–0.95)
NMSC	0 (0.00–1.82)	0.26 (0.01–1.47)	0.35 (0.23–0.50)
Other malignancies	0 (0.00–1.82)	0.26 (0.01–1.47)	0.43 (0.30–0.59)
MACE^c	0 (0.00–1.82)	0.26 (0.01–1.47)	0.33 (0.22–0.48)
IBD	0 (0.00–1.82)	0 (0.00–0.79)	0 (0.00–0.03)
Crohn disease/ulcerative colitis	0 (0.00–1.82)	0 (0.00–0.79)	0 (0.00–0.03)
Suicidal ideation and behaviour^b	0 (0.00–1.82)	0 (0.00–0.79)	0.10 (0.05–0.20)

CI, confidence interval; AE, adverse event; SAE, serious adverse event; NMSC, nonmelanoma skin cancer; MACE, major adverse cardiovascular event; IBD, inflammatory bowel disease. ^aIncludes all patients who received ≥ 1 dose of guselkumab; placebo and adalimumab crossover patients were included after crossover to guselkumab. ^bPatient-level analysis. ^cEvents identified based on clinical review.

Table 4

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Exposure-adjusted rates of events per 100 person-years (PY) of follow-up during the placebo-controlled period and through the end of the reporting period

	Placebo-controlled period		Through end of reporting period
	Placebo (95% CI)	Guselkumab (95% CI)	Guselkumab (95% CI)^a
Patients treated, n	544	1220	2891
Total PY of follow-up	165	378	8662
Median PY of follow-up	0.3	0.3	3.5
≥ 1 AE	341 (314–371)	346 (327–365)	169 (166–172)
AEs leading to discontinuation	9.69 (5.54–15.74)	5.02 (3.02–7.84)	1.59 (1.34–1.88)
≥ 1 SAE	6.66 (3.33–11.93)	6.34 (4.06–9.44)	5.26 (4.79–5.77)
Infections	83.61 (70.25–98.79)	95.92 (86.31–106.31)	65.92 (64.22–67.65)
Candida infections	1.82 (0.37–5.31)	0.53 (0.06–1.91)	0.60 (0.45–0.79)
Non-pathogen-specific fungal infections suspicious for Candida	0 (0.00–1.82)	0.53 (0.06–1.91)	0.10 (0.05–0.20)
Serious infections	1.21 (0.15–4.38)	1.06 (0.29–2.71)	0.88 (0.69–1.10)
Malignancy^b	0 (0.00–1.82)	0.53 (0.06–1.91)	0.74 (0.57–0.95)
NMSC	0 (0.00–1.82)	0.26 (0.01–1.47)	0.35 (0.23–0.50)
Other malignancies	0 (0.00–1.82)	0.26 (0.01–1.47)	0.43 (0.30–0.59)
MACE^c	0 (0.00–1.82)	0.26 (0.01–1.47)	0.33 (0.22–0.48)
IBD	0 (0.00–1.82)	0 (0.00–0.79)	0 (0.00–0.03)
Crohn disease/ulcerative colitis	0 (0.00–1.82)	0 (0.00–0.79)	0 (0.00–0.03)
Suicidal ideation and behaviour^b	0 (0.00–1.82)	0 (0.00–0.79)	0.10 (0.05–0.20)

	Placebo-controlled period		Through end of reporting period
	Placebo (95% CI)	Guselkumab (95% CI)	Guselkumab (95% CI)^a
Patients treated, n	544	1220	2891
Total PY of follow-up	165	378	8662
Median PY of follow-up	0.3	0.3	3.5
≥ 1 AE	341 (314–371)	346 (327–365)	169 (166–172)
AEs leading to discontinuation	9.69 (5.54–15.74)	5.02 (3.02–7.84)	1.59 (1.34–1.88)
≥ 1 SAE	6.66 (3.33–11.93)	6.34 (4.06–9.44)	5.26 (4.79–5.77)
Infections	83.61 (70.25–98.79)	95.92 (86.31–106.31)	65.92 (64.22–67.65)
Candida infections	1.82 (0.37–5.31)	0.53 (0.06–1.91)	0.60 (0.45–0.79)
Non-pathogen-specific fungal infections suspicious for Candida	0 (0.00–1.82)	0.53 (0.06–1.91)	0.10 (0.05–0.20)
Serious infections	1.21 (0.15–4.38)	1.06 (0.29–2.71)	0.88 (0.69–1.10)
Malignancy^b	0 (0.00–1.82)	0.53 (0.06–1.91)	0.74 (0.57–0.95)
NMSC	0 (0.00–1.82)	0.26 (0.01–1.47)	0.35 (0.23–0.50)
Other malignancies	0 (0.00–1.82)	0.26 (0.01–1.47)	0.43 (0.30–0.59)
MACE^c	0 (0.00–1.82)	0.26 (0.01–1.47)	0.33 (0.22–0.48)
IBD	0 (0.00–1.82)	0 (0.00–0.79)	0 (0.00–0.03)
Crohn disease/ulcerative colitis	0 (0.00–1.82)	0 (0.00–0.79)	0 (0.00–0.03)
Suicidal ideation and behaviour^b	0 (0.00–1.82)	0 (0.00–0.79)	0.10 (0.05–0.20)

Infections

EAIRs for infections were 95.9/100 PY (95% CI 86.3–106.3) and 83.6/100 PY (95% CI 70.2–98.8) in the guselkumab and placebo groups, respectively, through week 16, and 65.9/100 PY (95% CI 64.2–67.6) in guselkumab-treated patients over the long-term reporting period (Table 4). Nasopharyngitis and upper respiratory tract infections were the most commonly reported infections in both the short- and long-term follow-up periods. Nasopharyngitis EAIRs were 26.0/100 PY (95% CI 18.9–35.1), 28.8/100 PY (95% CI 23.6–34.7) and 21.1/100 PY (95% CI 20.2–22.1) in the placebo, short-term guselkumab and long-term guselkumab groups, respectively; upper respiratory infection EAIRs were 13.3/100 PY (95% CI 8.4–20.2), 17.2/100 PY (95% CI 13.3–21.9) and 11.9/100 PY (95% CI 11.2–12.7), respectively.

Serious infection EAIRs were low in the guselkumab [1.06/100 PY (95% CI 0.29–2.71); four events: appendicitis, bacterial prostatitis, erysipelas and lung abscess] and placebo [1.21/100 PY (95% CI 0.15–4.38); two events: acute cholecystitis and chronic cholecystitis] groups through week 16 and remained low with guselkumab treatment over the long-term follow-up [0.88/100 PY (95% CI 0.69–1.10); serious infections reported in more than one patient included cellulitis (n = 11; 0.13/100 PY, 95% CI 0.06–0.23), appendicitis (n = 9; 0.10/100 PY, 95% CI 0.05–0.20), pneumonia (n = 8; 0.09/100 PY, 95% CI 0.04–0.18), diverticulitis (n = 4; 0.05/100 PY, 95% CI 0.01–0.12), erysipelas (n = 4; 0.05/100 PY, 95% CI 0.01–0.12), abscess limb (n = 2; 0.02/100 PY, 95% CI 0.00–0.08), ovarian abscess (n = 2; 0.02/100 PY, 95% CI 0.00–0.08), prostatitis (n = 2; 0.02/100 PY, 95% CI 0.00–0.08), and pyelonephritis (n = 2; 0.02/100 PY, 95% CI 0.00–0.08)]. Serious infection EAIRs in guselkumab-treated clinical trial participants were lower than in the PSOLAR population (Figure 1).^18,20

Figure 1

Rates of events of interest per 100 person-years (PY) of follow-up [95% confidence interval (CI)] in the guselkumab (GUS) group through the end of the reporting period [reference: Psoriasis Longitudinal Assessment and Registry (PSOLAR), from 2007 to 2014 (n > 12 000; > 40 000 PY of follow-up) and from 2007 to 2020 (> 74 000 PY of follow-up); and MarketScan, from 2005 to 2011 (n > 40 000; > 119 000 PY of follow-up)]. (a) Serious infections; (b) malignancies other than nonmelanoma skin cancer (NMSC); and (c) major adverse cardiovascular events (MACE). ^aPatient-level analysis; ^bMACE identified based on clinical review (GUS clinical trials) and on standardized Medical Dictionary for Regulatory Activities queries (PSOLAR).

In the placebo-controlled period, Candida infections were reported for three patients in the placebo group [1.82/100 PY (95% CI 0.37–5.31); two events of vulvovaginal candidiasis, one event of oral candidiasis] and for two patients in the guselkumab group [0.53/100 PY (95% CI 0.06–1.91); one event of vulvovaginal candidiasis and one event of skin Candida]. Through the long-term treatment period, Candida infections reported in guselkumab-treated patients included vulvovaginal candidiasis (n = 23; 0.27/100 PY, 95% CI 0.17–0.40), skin Candida (n = 15; 0.17/100 PY, 95% CI 0.10–0.29), oral candidiasis (n = 9; 0.10/100 PY, 95% CI 0.05–0.20), Candida infection (n = 2; 0.02/100 PY, 95% CI 0.00–0.08), genital candidiasis (n = 2; 0.02/100 PY, 95% CI 0.00–0.08) and balanitis Candida (n = 1; 0.01/100 PY, 95% CI 0.00–0.06). Non-pathogen-specific fungal infections suspicious for Candida included vulvovaginal mycotic infection (n = 6; 0.07/100 PY, 95% CI 0.03–0.15), oral fungal infection (n = 2; 0.02/100 PY, 95% CI 0.00–0.08) and genital fungal infection (n = 1; 0.01/100 PY, 95% CI 0.00–0.06). There were no cases of serious candidiasis or candidaemia.

Among guselkumab-treated patients, there were no reported opportunistic infections and no cases of active TB. Across studies, 173 guselkumab-treated patients had LTBI at enrolment. Through the end of long-term follow-up, there were no cases of LTBI reactivation in any guselkumab-treated patients.

Malignancies

Through week 16 there were no reported malignancies in the placebo group, and the malignancy EAIR was low in the guselkumab-treated group [0.53/100 PY (95% CI 0.06–1.91), representing one patient with NMSC (0.26/100 PY, 95% CI 0.01–1.47); BCC considered doubtfully related to treatment] and one patient with malignancy other than NMSC [0.26/100 PY (95% CI 0.01–1.47); rectal adenocarcinoma, undiagnosed prior to enrolment but considered by the investigator to have probably been present before administration of study drug] (Table 4).

During long-term treatment, 30 guselkumab-treated patients (0.35/100 PY, 95% CI 0.23–0.50) had NMSC, including 13 patients with 19 NMSCs in VOYAGE 1 (12 BCC, seven SCC), 11 patients with 13 NMSCs in VOYAGE 2 (10 BCC, three SCC) and six patients with seven NMSCs in ECLIPSE (four BCC, three SCC). Across studies, the event-level BCC : SCC ratio was 2 : 1, suggesting no NMSC signal for immunosuppression in patients treated with guselkumab for up to 5 years.

Through the long-term reporting period, 37 guselkumab-treated patients (0.43/100 PY, 95% CI 0.30–0.59) had a malignancy other than NMSC. Malignancies reported in more than one patient included breast (n = 7), colorectal (n = 7), melanoma (n = 4, including two cases of melanoma in situ), prostate (n = 4), head/neck (n = 4), bladder (n = 2) and lymphoma (n = 2). Four of these patients (in VOYAGE 1 or VOYAGE 2) had a history of malignancy other than NMSC more than 5 years before enrolment and experienced a recurrent (n = 1) or new (n = 3) malignancy during the study; all cases were confounded by pre-existing risk factors. These cases are described in a separate publication.²³ EAIRs of malignancies other than NMSC in guselkumab-treated patients in the psoriasis clinical studies were consistent with or lower than those reported in analyses of PSOLAR and MarketScan data (Figure 1).^18–21

The number of malignancies other than NMSC and cervical cancer in situ among guselkumab-treated patients through the long-term reporting period (n = 37) was similar to the number (adjusted for age, sex and race) expected in the general US population (n = 41.5). The SIR for the guselkumab-treated group vs. SEER was 0.89 (95% CI 0.63–1.23).

Major adverse cardiovascular events

From week 0 to 16, there were no MACE in the placebo group; one guselkumab-treated patient (VOYAGE 1) had a nonfatal MI (0.26/100 PY, 95% CI 0.01–1.47) (Table 4). This patient smoked cigarettes, had a history of hyperlipidaemia and hypertension, and had a BMI of 35.3 kg m^–2.

Over the long-term reporting period, 29 events (0.33/100 PY, 95% CI 0.22–0.48) were reported in 28 guselkumab-treated patients, including 19 nonfatal MIs (0.22/100 PY, 95% CI 0.13–0.34), seven nonfatal strokes [0.08/100 PY (95% CI 0.03–0.17); one patient in the Japan registration study had two nonfatal strokes] and three cardiovascular deaths (0.03/100 PY, 95% CI 0.01–0.10). Most patients with MACE (68%, n = 19/28) had three or more cardiovascular risk factors at baseline, including all three patients who experienced cardiovascular death. Two of six patients who experienced nonfatal stroke had a previous stroke history, including the patient with two strokes in the Japan registration study. All 19 patients who experienced nonfatal MI had one or more of the following risk factors: hypertension, hyperlipidaemia, obesity or current/former smoker.

EAIRs of MACE (identified by clinical review) in guselkumab-treated patients in psoriasis clinical studies were lower than those (identified by standard MedDRA queries) in PSOLAR (Figure 1).^18–20

Inflammatory bowel disease

Across all studies and time periods, there were no cases of IBD, including Crohn disease and ulcerative colitis, in any guselkumab- or placebo-treated patients, including patients who crossed over from placebo to guselkumab (Table 4).

Suicidal ideation and behaviour

Through the long-term reporting period, nine guselkumab-treated patients had AEs of suicidal ideation and behaviour (0.10/100 PY, 95% CI 0.05–0.20; Table 4), including one completed suicide (0.01/100 PY, 95% CI 0.00–0.06), one suicide attempt (0.01/100 PY, 95% CI 0.00–0.06) and seven patients with suicidal ideation (0.08/100 PY, 95% CI 0.03–0.17). The completed suicide involved a patient with a medical history of depression and was considered unrelated to the study drug. The suicide attempt involved a patient with a medical history of anxiety, alcohol use and recent personal crises, and was considered unrelated to the study drug.

Hypersensitivity

Across all studies and time periods, there were no reported events of serum-sickness-like or anaphylactic reactions related to treatment with guselkumab.

Discussion

The safety profile of guselkumab in this analysis of pooled data from 2891 patients treated for up to 5 years (8662 PY) was favourable and consistent with previous reports. No new safety concerns were identified. Pooled results from studies with 16-week placebo-controlled periods showed similar rates of AEs with guselkumab and placebo. Although this analysis was limited by the short duration of the placebo-controlled period and lack of long-term comparator arms, the results showed that with long-term guselkumab treatment (median 3.5 years), the EAIRs of AEs, infections and AEs leading to discontinuation were comparable to or lower than those during the placebo-controlled period. While it is a known limitation that patients participating in long-term clinical trials tend to under-report AEs over time, in these phase II/III studies of guselkumab, discontinuations due to AEs were infrequent (≤ 6.1% in all studies), and high proportions of guselkumab-treated patients completed each study (78% in the 5-year VOYAGE studies;¹⁰ 84–95% in the five shorter studies),^11,14–17 indicating a consistent long-term safety profile that was not affected by patient dropout.

IL-23 and IL-17 are key proinflammatory cytokines in the pathogenesis of psoriasis. The IL-23/IL-17 axis also plays an integral role in host defence, including protection against fungal infections.²⁴ However, data suggest there are notable differences in the safety profiles of IL-23 and IL-17 inhibitors. The low rate of Candida infections (0.60/100 PY) in this analysis reinforces differentiation of the guselkumab safety profile from IL-17 inhibitors, which are associated with a higher incidence of candidiasis.^1,25 Pooled analyses of IL-17 inhibitors in psoriasis have reported Candida infection EAIRs of 14.2/100 PY (bimekizumab; > 3000 PY of follow-up),²⁶ 2.9/100 PY (secukinumab; > 15 000 PY)²⁷ and 1.9/100 PY (ixekizumab; > 17 000 PY).²⁸ Additionally, the observation of no cases of IBD during 8662 PY of guselkumab exposure reinforces the favourable gastrointestinal safety of IL-23 inhibition,^29–31 which is especially important given the increased risk of IBD in patients with psoriatic disease.³² In contrast, IL-17 inhibitors may be associated with an increased risk for IBD,³³ and use of IL-17 inhibitors in patients with personal history of or active IBD requires careful consideration.¹ Clinical studies of IL-17 inhibitors in IBD were terminated because of cases of worsening Crohn disease or lack of efficacy,^34,35 whereas IL-23 inhibitors have demonstrated efficacy in the treatment of moderately to severely active Crohn disease^36–38 and ulcerative colitis.³⁹ Furthermore, the low rates of suicidality AEs with guselkumab (0.10/100 PY) and other IL-23 inhibitors are noteworthy as the IL-17 receptor inhibitor brodalumab has labelled warnings for suicidal ideation and behaviour, including completed suicides,^30,31,40 although a causal relationship has not been established.^41,42

Historically, there have been concerns over using TNF-α inhibitors to treat psoriasis due to increased risks of TB and LTBI reactivation, which are important safety considerations, particularly in some geographical regions.^6,7,43 Across the seven pooled studies in this analysis, there were no cases of active TB, including no cases of TB reactivation among 173 guselkumab-treated patients with LTBI at enrolment. In-depth analyses from the VOYAGE studies showed that among 130 patients with LTBI, the most common prophylactic treatments were isoniazid (82%) and rifampicin (15%).⁴⁴ Consistent with known hepatotoxicity risks associated with these TB drugs,⁴⁵ elevated alanine and aspartate aminotransferase levels were more common in guselkumab-treated patients with vs. without LTBI; the majority of cases were common terminology criteria for AEs grade 1 or 2.⁴⁴ Two serious cases of new-onset active TB were observed in adalimumab-treated patients in VOYAGE 2,¹³ consistent with the known risk of TB with TNF-α inhibitor therapies.⁴³ Furthermore, while TNF-α inhibitors are associated with an increased risk of demyelinating disorders and are contraindicated in patients with multiple sclerosis and Guillain–Barré syndrome, no demyelinating disease safety signals have been reported in patients with psoriasis treated with IL-17, IL-12/23 or IL-23 inhibitors.^1,6,46,47

To provide real-world context, EAIRs of serious infections, malignancy and MACE in these pooled studies of guselkumab were compared to those derived from PSOLAR and MarketScan data. Overall, EAIRs were similar to or lower than those in guselkumab trials than in PSOLAR and MarketScan populations.^18–21 However, there are inherent limitations of comparing psoriasis clinical trial and real-world data because guselkumab clinical trial participants had to meet eligibility criteria related to psoriasis disease severity, previously used and concomitant medications, comorbidities and medical history. Nonetheless, the inclusion criteria in the guselkumab trials allowed for the enrolment of patients with comorbidities that are common in psoriasis populations. Based on the medical and treatment histories of patients in the guselkumab studies (Tables 2, 3), similar proportions had cardiovascular, psychiatric, endocrine and cancer-related comorbidities, as well as prior methotrexate use, compared to the PSOLAR population.⁴⁸ However, patients in the guselkumab trials were far more likely to be biologic-naïve at enrolment (75%) than in PSOLAR (28%).⁴⁸

Additional important limitations of this analysis include the unavoidable heterogeneity of the study durations, resulting in unequal PY contributions of each of the seven studies to the pooled dataset, and the need for longer-term real-world data to further elucidate the safety profile of guselkumab. PSOLAR, which has been expanded to include patients receiving guselkumab or an IL-17 inhibitor, will be an important source of guselkumab real-world safety data in the future (ClinicalTrials.gov NCT00508547).

In this pooled analysis in 2891 patients with psoriasis treated for up to 5 years, guselkumab demonstrated favourable safety, consistent with previous reports. Safety event rates in guselkumab-treated patients were similar to those observed with placebo and were consistent over long-term treatment.

Acknowledgements

Medical writing support was provided by Cherie Koch, PhD, of Janssen Scientific Affairs LLC, under the direction of the authors in accordance with Good Publication Practice guidelines (Ann Intern Med 2022; 175:1298–1304). The authors thank Cynthia Guzzo MD, a paid consultant for Janssen, for a substantive manuscript review.

Funding sources

These studies were funded by Janssen Research & Development, LLC and Janssen Pharmaceutical, Tokyo, Japan.

Data availability

The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA): http://yoda.yale.edu.

Ethics statement

All studies were conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with Good Clinical Practice. All study protocols were approved by an institutional review board or ethics committee. All participants provided written informed consent.

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