Safety and effectiveness of guselkumab in Japanese patients with psoriasis: 20‐week interim analysis of a postmarketing surveillance study

A 52‐week postmarketing surveillance study was initiated to evaluate the safety and effectiveness of guselkumab, a human anti–interleukin 23 subunit p19 monoclonal antibody, in Japanese patients with psoriasis vulgaris, psoriatic arthritis, generalized pustular psoriasis, and erythrodermic psoriasis in real‐world practice. Here, we report results of the 20‐week interim analysis of the ongoing postmarketing surveillance study. Patients who received guselkumab between May 2018 (the date of commercial launch in Japan) and October 2020 were registered in this study. In total, 411 and 245 patients were included in the safety and effectiveness analysis sets, respectively. Adverse drug reactions (ADRs) occurred in 6.6% (27 of 411) and serious ADRs in 2.2% (nine of 411) of patients. The most frequent ADRs by System Organ Class were “Infections and infestations” (2.4%), with nasopharyngitis being the most frequently observed ADR (0.7%). The mean Psoriasis Area Severity Index score decreased from 11.6 at baseline to 6.5 at week 4 and 2.2 at week 20, with improvements achieving statistical significance at each time point. Clinical Global Impression, Dermatology Life Quality Index, and Nail Psoriasis Severity Index outcomesalso showed substantial improvements. Our findings demonstrate that guselkumab is well tolerated and effective in Japanese patients with psoriasis through 20 weeks of treatment in real‐world clinical practice, showing significant effectiveness observed as early as 4 weeks. The study was officially registered with the University Hospital Medical Information Network Clinical Trials Registry with the identifier UMIN000032969.

than 10 biologics that target various cytokines, along with new smallmolecule therapeutics such as phosphodiesterase-4, Janus kinase, and tyrosine kinase 2 inhibitors, for treating psoriasis with cytokine-driven inflammation.In Japan, the first biologics for psoriasis were infliximab and adalimumab (anti-tumor necrosis factor α [TNFα] antibodies) introduced in 2010, followed by ustekinumab (anti-interleukin 12/ IL-23 subunit 40 [IL-p40] antibody) in 2011.Since 2015, a variety of other biologics have become available including secukinumab and ixekizumab (anti-IL-17A antibodies), brodalumab (anti-IL-17R antibody), guselkumab (GUS), risankizumab and tildrakizumab (anti-IL23p19 antibodies), certolizumab pegol (anti-TNFα antibody Fab fragment), and bimekizumab (anti-IL-17A/F antibody).6][7][8] The Japanese guidance on the use of biologics for the treatment of psoriasis from the Japanese Dermatological Association (JDA) states that it is important for physicians to select appropriate biologic therapy for each patient with psoriasis after due consideration of disease factors, treatment factors, and patient background factors, sharing such information with patients.The JDA guidance also notes that when selecting biologics, factors to be considered include not only the drug's effectiveness (such as likelihood of high level response, time to onset of effectiveness, effectiveness against arthritis, and failure rates) but also safety (such as the risk of infections, administrationrelated reactions, and potential for exacerbating comorbidities), convenience for patients (e.g.hospital visit intervals, self-injection, maintenance therapy at clinics, feasibility of drug discontinuation/readministration), and payment (medical costs) borne by patients. 80][11][12][13] In 2018, GUS was approved in Japan for the treatment of patients with psoriasis vulgaris (PsV), psoriatic arthritis (PsA), generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP), who have not adequately responded to conventional therapies.The ongoing postmarketing surveillance (PMS) study, which was required by the Pharmaceuticals and Medical Devices Agency (PMDA) as part of the Risk Management Plan and Pharmacovigilance Plan for GUS approval, has been planned and is being conducted to assess the safety and effectiveness of GUS in Japanese patients with psoriasis in clinical practice over a period of 52 weeks.This report presents results from the 20-week interim analysis of the PMS for GUS in real-world patients with psoriasis.
Although randomized controlled trials are generally considered the gold standard for evaluating the safety and efficacy of new treatments, strict inclusion and exclusion criteria often result in trial populations that are not representative of real-world patients who may have comorbidities and use other concomitant medications. 14erefore, real-world studies are becoming increasingly important to provide evidence supporting treatment safety and effectiveness in actual clinical settings. 14,15[17][18][19][20] This interim analysis provides valuable insights into the characteristics of Japanese patients with psoriasis treated with GUS in real-world clinical practice and early safety and effectiveness outcomes with GUS treatment.The results of this analysis are expected to inform ongoing discussions on the appropriate use of biologics for psoriasis in Japan.

| Study design
This is a multicenter, single-arm, prospective, observational longitudinal follow-up cohort study in patients with PsV, PsA, GPP, and EP who initiated treatment with GUS in Japan.The observation period is 52 weeks after the initial dosing of GUS.GUS is administered by subcutaneous injection at a dose of 100 mg at weeks 0 and 4 followed by maintenance dosing with 100 mg every 8 weeks (Figure 1).This is the interim report for a series of analyses of the ongoing study.This 20-week interim analysis report presents results for patients who initiated treatment with GUS between May 2018 and October 2020.

| Data collection and outcomes
Patient demographic and other baseline characteristics including medical history and comorbidities, as well as information pertaining to GUS treatment and concomitant drugs, were collected throughout the observation period.Investigators recorded adverse events (AEs), serious AEs, adverse drug reactions (ADRs; defined as AEs for which a causal relationship to drug treatment cannot be ruled out), and serious ADRs (SADRs) for safety assessments.AEs were coded by System Organ Class (SOC) and Preferred Term using Medical Dictionary for Regulatory Activities (MedDRA) version 25.0.Based on the Risk Management Plan for GUS, serious infections and serious hypersensitivity reactions were categorized as "important identified risks," while malignancy, decreased neutrophil count, and major adverse cardiovascular events were classified as "important potential risks" for safety assessments.
The Psoriasis Area Severity Index (PASI), Clinical Global Impression (CGI) measure, which is evaluated by the treating clinician based on five potential responses (very much improved, much improved, minimally improved, no change, and worse), 21 Dermatology Life Quality Index (DLQI), 22 and Nail Psoriasis Severity Index (NAPSI) 23 were used for assessment of effectiveness (Figure 1).

| Statistical analysis
Safety evaluations were based on the safety analysis set, which included patients eligible for this study but excluded those with protocol violations, incomplete case report forms, and invalid case report forms.Effectiveness evaluations were based on the effectiveness analysis set, which consisted of patients in the safety set but excluded patients with missing or incomplete data on effectiveness evaluations.
Statistical analyses for the safety and effectiveness end points were performed on the safety analysis set and effectiveness analysis set, respectively.Change from baseline in PASI, DLQI, and NAPSI scores was assessed with the pairwise t test without multiplicity adjustment.Analyses were conducted to examine the influence of patient factors on PASI 90 response by estimating odds ratios and 95% confidence intervals using a logistic regression model, considering both crude (univariate) and adjusted (multivariate) values.In addition, the Wald test was used to calculate P values for odds ratios.
Missing values were not imputed.
All statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc.), in accordance with the user's manual.

| Patient demographics and baseline characteristics
In total, 428 patients with psoriasis were registered during the enrollment period.Case report forms of 419 patients were available for the 20-week interim analysis.Nine case report forms were uncollected.As eight patients with protocol violations and incomplete data were excluded, the safety analysis set consisted of 411 patients.
The effectiveness analysis set comprised 245 patients, after excluding 166 patients from the safety analysis set due to incomplete data on effectiveness evaluations (Figure 2).Table 1 summarizes the demographic and baseline characteristics of patients in the safety analysis set.There were more male patients (65.7%), and the mean age ± standard deviation was 57.8 ± 15.2 years.There were 152 (37.0%) elderly patients older than 65 years, with the oldest being 97 years.There were 307 (74.7%), 73 (17.8%), 26 (6.3%), and five (1.2%) patients who received GUS treatment for PsV, PsA, GPP, and EP, respectively.The mean duration of psoriasis was 13.9 ± 10.5 years.A total of 150 (36.5%) patients reported a disease duration of <10 years, and 84 patients had a disease duration of <5 years.while the most commonly used biologics were ustekinumab (UST; 22.1%), followed by secukinumab (SEC; 10.2%).
Major comorbidities reported for study patients are presented in Table 2. Overall, 53.5% of patients had one or more comorbidity, including hypertension (20.9%), diabetes (10.9%), hyperuricemia (5.6%), dyslipidemia (4.9%), and hyperlipidemia (4.6%).Among six patients with hepatitis B virus (HBV), five had HBV-DNA levels below the limit of quantification (one patient was untested) and one had received a DNA analog before starting GUS because of a positive hepatitis B antigen test.No patient had active tuberculosis (TB).Regarding latent TB, among 324 patients who underwent either a tuberculin reaction test or an interferonγ release test, eight patients were found to be positive for the tuberculin test, while six tested positive for the interferonγ release test.In addition, five patients in each group had received prophylactic anti-TB drugs.Among the 239 patients for whom chest computed tomography scans were performed, no evidence of current or past TB infection was found.

| Safety
The incidence of ADRs over the 20-week analysis period is presented in Table 3 AEs leading to treatment discontinuation were reported for 10 patients, with six of these assessed as treatment related.Among the treatment-related cases, four were SADRs (erythrodermic psoriasis, interstitial lung disease, pneumonia, and aspergilloma), while the other two cases (alopecia and pruritus) were nonserious.No deaths were reported through week 20.

| Effectiveness
This analysis also aimed to evaluate the effectiveness of GUS in patients with psoriasis.For the effectiveness analysis population  3a).Significant improvements were observed for both PsV and PsA patient groups, with mean PASI scores of 11.9 and 10.4 at baseline, respectively, decreasing to 6.5 and 6.1 at week 4, and 2.1 and 2.6 at week 20 (Figure 3b).
Moreover, although mean PASI scores at baseline were 8. provements in mean PASI scores were observed between the two groups (Figure S2).
The results depicted in Figure 5a demonstrate that mean DLQI score decreased significantly from 7.7 at baseline to 4.3 at week 4 and 2.5 at week 20.Moreover, by week 20, 56.5% of patients with PsV achieved a DLQI score ≤1, indicating no effect of psoriasis on quality of life.In addition, 89.9% of patients achieved a DLQI score ≤5, signifying either no effect or only a slight effect on their quality of life (Figure 5b).
Patients who were determined to be "very much improved," "much improved," or "minimally improved" based on their CGI score were considered treatment responders.Among all patients in the effectiveness analysis set, the CGI response rates were 83.0% at week 4 and 92.0% at week 20 (Figure 6).
Nail lesions were evaluated using the NAPSI.A clear decrease in mean NAPSI score from 4.0 at baseline to 2.0 at week 20 was observed for the overall study group.The severity of nail psoriasis was reduced for both the PsA and PsV patient subgroups, with notable improvements in mean NAPSI score from 3.3 and 4.1 at baseline to 1.2 and 2.6 at week 20, respectively (Figure 7).
Univariable and multivariable analyses (Figure S3) suggest that certain factors, such as a lower baseline PASI score and switching from a prior biologic treatment, were associated with a lower likelihood of achieving PASI 90.This interim PMS analysis provides real-world insights on the safety and effectiveness of GUS over the initial 20 weeks of treatment for patients with psoriasis in Japan.Real-world studies, such as those for PMS purposes, are more likely to include elderly patients and those with prior treatment experience, who tend to be underrepresented in clinical trials. 18,20Our study reflects this trend with a higher mean age of 57.8 years compared with 47.8 years in the Japanese Phase III PSO3004 trial for GUS in psoriasis. 12Moreover, our study found a  In addition, 23.6% of our study participants had ever previously used APR, which has become the most prescribed oral medication for psoriasis since 2017 based on an annual survey performed by the Japanese Society for Psoriasis Research. 24In the PSO3004 study, none of the patients in the GUS 100-mg group had prior experience with APR because APR was approved after PSO3004 enrollment.
Variations in treatment trends and the transformative impact of biologics on psoriasis treatment over the past decade 24    a comprehensive understanding of treatment outcomes in diverse patient populations.
In our study, we found that 53.5% of the enrolled patients had at least one comorbidity.[29][30] PsA represents a major comorbidity associated with psoriasis typically preceding onset of joint symptom by several years in patients with PsA.In our PMS study 17.8% of patients received GUS for treating PsA.Recently, the concept of psoriatic disease (PsD) has been proposed, a systemic condition encompassing PsO and PsA, but also extends to include other key comorbidities such as metabolic syndrome, type 2 diabetes, and hypertension. 313][34] Considering the prevalence of comorbidities in our study population and the concept of PsD management, we believe that close monitoring and early intervention using targeted therapeutics such as biologics may potentially have a positive impact on prognosis and prevention of new comorbidities, [35][36][37][38][39] particularly in patients with high disease activity. 4,40Adopting holistic and long-term-oriented treatment strategies could further optimize the benefits for patients.
2][13]16,18 These findings further support the overall safety profile of GUS in real-world settings.
In In addition, the subgroup analysis provides new insights into the effectiveness of GUS among patients switching from APR.Previous reports 43,44  In consideration of the findings reported here, certain limitations to the study must be acknowledged.In this observational study, there was no control group and it included patients with different types of psoriasis resulting in a heterogeneous study population.Further, the small proportion of patients with PsA, GPP, and EP limited analysis of each specific disease group in this interim analysis.In addition, this analysis was limited to a 20-week evaluation period, and further long-term analyses are necessary.Despite these limitations, the strengths of this study are its prospective design, multicenter approach, and large cohort of Japanese patients with psoriasis.This study benefited from the collaboration of more than 80 sites across Japan, and the demographic characteristics of the study population did not differ notably from those reported in a prior epidemiological study of Japanese patients with psoriasis. 24Therefore, the safety and effectiveness findings for GUS in this study could be considered representative for the broader psoriasis patient population in realworld clinical practice in Japan.
In conclusion, this 20-week interim analysis of the GUS PMS study in Japan found no new safety concerns.In addition, the favorable effectiveness profile of GUS in patients with psoriasis, including those who switched to GUS from APR and a biologic, was reaffirmed.However, longer-term data from this ongoing study and other sources are needed to better understand the safety and effectiveness profile of GUS in Japanese patients with psoriasis.

ACK N OWLED G M ENTS
The authors wish to thank the patients who participated in this study and the investigators who contributed to its execution.The authors also take complete responsibility for the integrity of the data and accuracy of the data analysis.This study was funded by Janssen Pharmaceutical K.K., Tokyo, Japan.

CO N FLI C T O F I NTE R E S T S TATE M E NT
Y.
The protocol, including all ethical aspects, was submitted for internal review board approval and confirmed by PMDA.The study is conducted in accordance with the Japanese regulations for Good Post-Marketing Study Practice, as specified by the Ministry of Health, Labour and Welfare Ministerial Ordinance no.171.Initiation of the study occurred following establishment of a contract between the participating institutions and Janssen Pharmaceutical KK in Tokyo, Japan.F I G U R E 1 Study design.CGI, Clinical Global Impression; DAS28, Disease Activity Score in 28 Joints; DLQI, Dermatology Life Quality Index; NAPSI, Nail Psoriasis Severity Index; PASI, Psoriasis Area Severity Index.

3 and 14 . 4
Figure3d, FigureS1).A total of 15 patients who received cyclosporine (CyA) before starting GUS were evaluated separately; 10 patients discontinued CyA before starting GUS, whereas five patients continued CyA after initiating GUS.Comparable im-

F I G U R E 3
Psoriasis Area Severity Index (PASI) score (mean and standard deviation [SD]) at baseline and weeks 4, 12, and 20.(a) Overall.(b) Patients with psoriasis vulgaris (PsV) and psoriatic arthritis (PsA).(c) Patients with and without prior biological treatment.(d) Patients switched from apremilast (APR) treatment by reasons for switching.*p < 0.05 by pairwise t-test for change from baseline PASI score by each time.

F I G U R E 5
(a) Dermatology Life Quality Index (DLQI) score (mean and standard deviation [SD]) at baseline and weeks 4, 12, and 20 in patients with psoriasis vulgaris (PsV).*p< 0.05 by pairwise t-test for change from baseline DLQI score by each time.(b) Proportions of patients with PsV achieving DLQI responses.A DLQI score level of 0 or 1 represents no effect of psoriasis on quality of life; 2 to 5, small effect; 6 to 10, moderate effect; 11 to 20, very large effect; and 21 to 30, extremely large effect.(a) DLQI score (mean SD) at baseline, and weeks 4, 12 and 20 in patients with PsV (b) terms of effectiveness, our study demonstrated significant reductions in PASI score as early as 4 weeks and at 12 and 20 weeks after initiating GUS treatment.Significant improvements in PASI score were observed not only in the overall patient population but also in various subgroups, including those comprising patients with PsV, with PsA, with or without prior exposure to biologic therapies, as well as subgroups of patients who switched from APR or a biologic to GUS.After 20 weeks of GUS treatment, mean PASI scores ranged from 2.1 to 2.6 across the above-mentioned subgroups.These outcomes underscore the consistent effectiveness of GUS in treating psoriasis, regardless of variations in patient profiles.The efficacy of GUS across diverse patient subgroups has also been demonstrated in phase 3 trials of VOYAGE 1 (A Study of Guselkumab in the Treatment of Participants With Moderate to Severe Plaque-Type Psoriasis) and VOYAGE 2 (A Study of Guselkumab in the Treatment of Participants With Moderate to Severe Plaque-Type PsoriasisWith Randomized Withdrawal and Retreatment).41Moreover, in recent years, consideration of the absolute PASI scores has been increasingly recognized as an important measure for assessing treatment effectiveness in clinical practice.Achieving an absolute PASI score below the threshold of 2 or 3 holds considerable clinical importance, representing a concrete and clinically meaningful reduction in symptoms.42Noticeably, our findings highlight how GUS treatment effectively enables the achievement of this high level of response, which is well-aligned with established treatment goals.
Incidence of ADRs during the initial 20 weeks of the observation period (N = 411) TA B L E 3

PsV and PsA patients
(c)

Achievement of PASI 75/90/100 response in patients with PsV (b) Absolute PASI response rates in patients with PsV
ing to the lower baseline PASI score and BSA compared with the PSO3004 trial (mean PASI scores: 11.6 vs 26.7; mean BSA: 22.7% vs 37.9%).In addition, the inclusion of a pretreatment washout period in the PSO3004 trial may have led to the higher baseline PASI score and BSA compared with the real-world PMS study.These findings underscore the value of real-world data in gaining F I G U R E 4 (a) Achievement of Psoriasis Area Severity Index (PASI) 75/90/100 response in patients with psoriasis vulgaris (PsV).(b)Absolute PASI response rates in patients with PsV.(a)

Proportions of patients with PsV achieving DLQI responses
Clinical Global Impression (CGI) assessments at week 20.