Safety, efficacy, and drug survival of the infliximab biosimilar CT‐P13 in post‐marketing surveillance of Japanese patients with psoriasis

Abstract Based on extrapolation of similar clinical outcomes in rheumatoid arthritis to the originator infliximab (IFX) in randomized clinical trials, the first biosimilar antibody CT‐P13 was approved for the treatment of psoriasis. To evaluate the safety, efficacy, and drug survival of CT‐P13 for psoriasis in real‐world clinical practice, prospective post‐marketing surveillance was conducted in 165 Japanese psoriasis patients. During a 1‐year follow‐up period, adverse drug reactions (ADRs) occurred in 29 patients (17.6%). Infusion reaction was the most frequent ADR (6.7%), and mild pneumonia was reported as the only case of infection. Serious ADRs were reported in two patients (1.2%): acute cholecystitis and interstitial pneumonia. The interstitial pneumonia developed after a single infusion of CT‐P13 and the patient died of respiratory failure. In naive patients to biologic therapy (n = 44), the Psoriasis Area Severity Index (PASI) decreased rapidly after the start of CT‐P13 treatment, and response rate achieving an absolute PASI score <1 was 55% at 30 weeks. The response rate was high (78%) in patients with psoriatic arthritis, and 40% and 20% in those in plaque psoriasis and pustular psoriasis, respectively. Of patients switched from IFX to CT‐P13 mainly for nonmedical reasons (n = 105), 57% had already reached PASI <1 by pretreatment with IFX and CT‐P13 maintained this status. The incidence of ADRs in this patient group was low and the drug survival rate was as high as 74%, even at 1 year, which was significantly higher than that in the naïve patient group (47%). Patients switched from other biologics for medical reasons (n = 16) responded similarly to biologic‐naïve patients, but drug survival was lower (24%). In conclusion, CT‐P13 showed excellent effectiveness as a first‐line therapy, no clinical difficulties in switching from IFX, and usefulness in patients who failed other biologics. CT‐P13 could be a cost‐effective alternative to IFX for the treatment of psoriasis.

CT-P13, the first approved IFX biosimilar, was developed to reduce the economic burden on healthcare and improve patient access to treatment. In randomized controlled clinical studies comparing IFX and CT-P13 in patients with rheumatoid arthritis and ankylosing spondylitis, the pharmacokinetics, safety profile, and efficacy of CT-P13 were comparable to those of IFX. [2][3][4][5] CT-P13 was approved for the treatment of various inflammatory diseases, including inflammatory bowel disease and psoriasis, by extrapolation without undergoing clinical trials. After its approval, two randomized controlled studies and several observational clinical studies demonstrated a similar safety profile, immunogenicity, and comparable efficacy to the originator IFX. [6][7][8][9] However, studies of CT-P13 in psoriasis patients are few and include only a limited number of patients. 6,10,11 In 2014, we initiated a series of prospective post-marketing surveillance (PMS) studies of CT-P13 in a variety of Japanese patients and reported the interim results of the PMS in rheumatoid arthritis and inflammatory bowel disease. [12][13][14] Here we present the PMS results regarding the safety, efficacy, and drug survival of CT-P13 in 165 Japanese patients with psoriasis. In this report, we first analyzed the clinical effects of CT-P13 in biologic-naïve patients with four types of psoriasis and compared them with previous PMS data of the originator IFX. 15 Second, we examined whether switching to CT-P13 from IFX is acceptable in terms of safety and maintaining clinical effectiveness. Third, we explored the clinical effects of CT-P13 in patients who switched from previous treatment with other biologics due to an inadequate response or adverse events (AEs). In addition, we identified clinical risk factors for adverse drug reactions (ADRs) and predictors for the efficacy of CT-P13 by multivariable logistic regression analyses.

| Post-marketingsurveillance
Nippon Kayaku Co., Ltd initiated PMS in patients with psoriasis after the approval of CT-P13 in Japan. Patients were enrolled prospectively from July 2014 to December 2019 and were followed up for 1 year after the start of CT-P13 therapy. To minimize patient selection bias, we used a centralized system for registering all patients at the contracted clinical sites. Patients were defined as those with psoriasis unsuccessfully treated with conventional therapies and who received treatment with CT-P13 according to the Japanese Dermatological Association's 2013 guidance for use of biologics for psoriasis. 16 The CT-P13 regimen was recorded and changes in the scheduled dosage and dosing interval were reported along with the reasons for those changes. Case report forms were collected from each patient at 6 months and 1 year after the start of treatment.  (Code IFX22) were assessed by internal review board members and approved by the MHLW, and no additional formal ethics committee approval was needed. The PMS was conducted in accordance with the Good Postmarketing Study Practice Ordinance of the MHLW and informed consent from individual patients was not required.

| Safety
All AEs, including subjective/objective findings and laboratory test data, were collected and the causal relationship of AEs to CT-P13 was evaluated. AEs and ADRs for which a causal relationship with CT-P13 was not ruled out were coded in accordance with the System Organ Class and Preferred Term listed in the Medical Dictionary for Regulatory Activities (MedDRA/J; version 24.0). ADRs of particular interest were infusion reaction, serious infections (including tuberculosis), interstitial lung disease, and malignant neoplasms.

| Efficacy
The efficacy of CT-P13 for psoriasis was evaluated by the absolute Psoriasis Area Severity Index (PASI) (graded 0, <1, <2, <5, ≥5), as well as the PASI response to achieve a reduction in the baseline PASI (PASI 100, 90, 75, 50). 17 Physician's Global Assessment (PGA) scores of 0 or 1 (clear or almost clear) and a Dermatology Life Quality Index (DLQI) <1 were also considered to indicate effectiveness. 18,19 Effects on joint symptoms in psoriatic arthritis patients were also evaluated according to the Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) with cut-off values for high, moderate, and low disease activity of 5.1, 3.2, and 2.6, respectively. The European League Against Rheumatism (EULAR) response criteria, with cut-off decreases in DAS28 of 0.6 and 1.2, were also applied for evaluation. 20,21 The data obtained on the nearest day to the scheduled administration time points (weeks 2, 6, and every 8 weeks thereafter for IFXnaïve patients, and every 8 weeks for patients switched from IFX to CT-P13) were used as the representative values.

| Statisticalanalysis
The drug survival of CT-P13 was plotted using the Kaplan-Meier method, with the last administration as an event. Patients who discontinued treatment with CT-P13 after a single dosing were excluded from the plots. Differences between patient groups were analyzed using the log-rank test.
Univariate analysis followed by multivariable analysis was performed using a logistic regression model to explore risk factors for the occurrence of infusion reactions and other ADRs. The logistic regression model was also applied for efficacy analysis to find pre- The odds ratio (OR) and the two-sided Wald 95% confidence interval (95% CI) were estimated for each covariate.

| Patientcharacteristics
In this prospective PMS of CT-P13, 168 patients were registered, but case report forms for three patients were not available. The 165 patients who received at least one infusion of CT-P13 were included in the safety analysis set and had been followed up for 1 year.
Evaluable efficacy data were missing from eight patients, and 157 patients were included in the efficacy analysis set ( Figure S1).
Representative patient characteristics, disease status, prior therapy, and concomitant medications are summarized in Table 1. Approximately 70% of the patients in each group were male, and the average age of each group was similar (mid-50s). Patients with psoriatic arthritis had a shorter disease duration and lower disease status. For psoriatic arthritis, prior treatment with cyclosporine, topical steroids and vitamin D, and phototherapy was less frequent.
Concomitant use of topical steroids, vitamin D, and phototherapy was also infrequent in psoriatic arthritis patients, although MTX was combined in 49% of patients in this group. In patients with pustular psoriasis, the disease duration was longer, comorbidities were commonly observed (75%), and the disease status was severe.
In the naïve patient group, the average PASI, body surface area (BSA), and DLQI were 11.6, 27.2%, and 9.8, respectively, and 66% were considered to have severe psoriasis according to the rule of 10s (PASI >10, BSA >10% or DLQI >10). 22 In contrast, in the group of patients who switched from IFX, all disease scores were low and only 8% of patients had severe psoriasis. Most of those patients (88%) had been treated with IFX alone as the first biologic therapy. The dose of CT-P13 was almost the same as the last dose of IFX in most patients, but was increased to the higher from the standard dose of IFX in four patients and reduced to the standard dose of IFX dose in three patients. The disease status of patients who switched from other biologics was less severe than that of naïve patients, but 36% of patients had severe disease. Topical steroids or vitamin D were infrequently prescribed for these patients in pretreatment as well as in combination with CT-P13. Approximately one-third (38%) of the patients experienced treatment failure with at least two previous biologics before switching to CT-P13.

| Incidenceofadversedrugreactions
Of the 165 patients in the safety analysis set, 44 AEs (26.7%) and eight serious AEs (4.8%) were reported during the 1-year followup period ( Table 2). Among them, ADRs and serious ADRs were observed in 29 (17.6%) and two patients (1.2%), respectively. The most common ADR was infusion reaction (n = 11 patients, 6.7%), and although there were no serious cases, five patients discontinued treatment. In the infection category, only one case of pneumonia was reported. The patient developed pyrexia after seven doses of CT-P13, but the symptoms were mild and resolved with antibiotics, and administration of CT-P 13 was continued after a 4-week delay. Tuberculosis did not occur. Examination for tuberculosis (tuberculin skin test, interferon gamma release assay, chest radiograph, and computed tomography) before CT-P13 administration was performed in all but one patient. Interstitial pneumonia occurred in three patients. Two patients recovered after discontinuing CT-P 13 without treatment, but one naive patient with psoriatic arthritis developed serious interstitial pneumonia 12 days after the first infusion of CT-P13 following oral MTX at 8 mg/week for 12 days. Despite repeated pulse therapy with steroids and cyclophosphamide, the patient died of respiratory failure 45 days after administration. He was 59 years old with a 45-year history of smoking, but no abnormalities were found on previous chest radiography and computed tomography. He had no comorbidities or past medical history, and no disorder was recorded in the medical interview. The causal relationship to CT-P13 and/or MTX was reported to be unknown. The other serious ADR was acute cholecystitis. After the fifth dose of CT-P13, the patient was hospitalized with fever and arthralgia. Abdominal computed tomography showed swelling of the gallbladder and gallstones in the gallbladder neck, and the patient recovered following antibiotic administration. Neoplasms were found in three patients during the observation period, but all were considered unrelated to CT-P13. All reported AEs and ADRs classified by the System Organ Class are listed in Supporting Information Table S1.
Among psoriasis types, the incidence of ADRs in psoriatic arthritis patients was low (13.5%). While the incidence of ADRs in biologic-naïve patients was 31.8%, that in patients who switched from IFX was 11.4%.

| RiskfactorsforADRs
Univariate and multivariable logistic regression analyses were performed for infusion reactions and other systemic ADRs separately, as the characteristics and onset time differed (Supporting Information Table S2 and Table 3). In the multivariable analysis, the incidence of an infusion reaction was significantly lower in patients who switched from IFX than in naïve patients (OR = 0.43, 95% CI 0.08-2.42, Prior therapy Prior biologics although no significant associations were detected in the multivariable analysis.

| Efficacybypsoriasistype
The efficacy of CT-P13 for three psoriasis types was evaluated by changes in the PASI, PGA, and DLQI in biologic-naive patients in the efficacy analysis set ( Figure 1). In plaque psoriasis, the proportion of patients with an absolute PASI of 0 gradually increased after the initiation of CT-P13 therapy. In psoriatic ar- General disorders and administration site conditions Injury, poisoning, and procedural complications 12 Respiratory, thoracic, and mediastinal disorders 9 Skin and subcutaneous tissue disorders

AEs/ADRs of particular interest
Infusion reaction 11 Neoplasm benign, malignant and unspecified a 3 Note: Data are expressed as patient number with AE/ADR (%).
Abbreviations: ADR, adverse drug reaction; AE, adverse event; IFX, infliximab; SOC, system organ class. a Squamous cell carcinoma of skin, metastasis to lymph nodes of breast cancer, and lymphoproliferative disorder.
subjective patient-reported outcomes were inconsistent between these types of psoriasis.
In these three types of psoriasis, CT-P13 was evaluated to be markedly effective, but its efficacy for psoriatic erythroderma could not be clearly determined because there were only two patients.
Nevertheless, one patient with psoriatic erythroderma showed a good response to CT-P13, and both the PASI and DLQI reached 0 from 54 and 12 at baseline, respectively. In the other patient, the baseline PASI 15 and DLQI 11 did not decrease and CT-P13 was switched to secukinumab after 4 weeks.

| Efficacybyprevioustreatmentstatus with biologics
The efficacy of CT-P13 was evaluated in three patient groups: naïve patients to biologics, patients switched from IFX, and patients switched from other biologics (Figure 2

| Efficacyforjointsymptomsinpatientswith psoriatic arthritis
In patients with psoriatic arthritis, the efficacy of CT-P13 for joint symptoms was also evaluated based on the change in the DAS28-CRP (Supporting Information Figure S2). and 88% showed a good or moderate EULAR response. In contrast, the DAS28-CRP of patients switched from IFX was already low (1.6) before starting CT-P13, and remission was obtained in 90% of patients due to prior treatment with the originator IFX.
The DAS28-CRP in these patients decreased further to around 1, but the low baseline value limited the margin for producing a good EULAR response.

| Efficacybybodyregion
Comparison of the efficacy of CT-P13 in each body region showed that the highest PASI 100 response rate was in the head (53%) followed by the arms and trunk (40% and 41%, respectively). Efficacy in the legs was lowest, with only 30% of patients achieving PASI 100 in the legs (Supporting Information Figure S3).

| Predictorsforefficacy
We explored the association of clinical factors with the response to CT-P13 by univariate and multivariable logistic regression analysis (Supporting Information Table S3 and Figure 3). The response rate for reaching an absolute PASI <1 was higher in male patients than in female patients (63% vs 53%) and male sex was a significant factor associated with a response in multivariable analysis (OR = 4.28, 95%

| Drugsurvivalandreasonsfordrug discontinuation
The Kaplan-Meier curve of drug survival for patients with plaque psoriasis was almost the same as that for patients with psoriatic arthritis and drug survival rates after 1 year were approximately 60% ( Figure 4a). Only two patients with pustular psoriasis discontinued CT-P13 and the drug survival rate was significantly higher (90%) for pustular psoriasis.
Drug survival in patients switched from IFX was significantly higher compared with the other two patient groups and 74% of the patients were on CT-P13 therapy at week 56 ( Figure 4b).  to continue CT-P13 therapy, even though they failed to respond to the initial regimen. The discontinuation rate due to insufficient efficacy was 44%, and ADR leading to drug discontinuation was observed only in one patient (6%) under the augmented dose regimen (Supporting Information Table S4).

| DISCUSS ION
This is the first report on the prospective PMS of a biosimilar in Japanese patients with psoriasis in real-world clinical practice. In the safety analysis, the incidence of ADRs of CT-P13 was 17.6%, which was lower than the previously reported incidence of 22.5% for IFX in PMS. 15 The incidence of serious ADRs was also lower with CT-P13 (1.2%) than IFX (6.9%), even though the observation period in this PMS was 1 year compared with 6 months in the former PMS.
The lower ADR incidence of CT-P13 in this PMS might be due to the higher proportion of patients with psoriatic arthritis among the four types of psoriasis (63% vs 32% in the PMS of IFX) and of patients previously treated with IFX before PMS entry (64% vs 4%). Japanese guidance for the use of biologics for psoriasis recommends starting treatment with TNF inhibitors from an early stage for patients F I G U R E 3 Multivariable logistic regression analysis of baseline clinical factors associated with response to CT-P13, that is achieving an absolute PASI <1 between 14/16 and 30/32 weeks after CT-P13 administration. *p < 0.05, **p < 0.01. BMI, body mass index; CI, confidence interval. PASI, Psoriasis Area and Severity Index.

F I G U R E 4
Kaplan-Meier plot of drug survival of CT-P13 in patient groups classified by (a) type of psoriasis and (b) prior treatment status with biologics. Patients who discontinued treatment with CT-P13 after a single dose were excluded from the plot. Statistical significance was analyzed by the log-rank test. *p < 0.05, **p < 0.01. IFX, infliximab; NS, not significant.
with psoriatic arthritis to prevent the progression of joint destruction. 16 In fact, patients with psoriatic arthritis in this PMS had the shortest disease duration (14.9 years) and the lowest proportion of severe disease (18%) among the four types of psoriasis. Among patients who switched from IFX, those who were sensitive to IFX were virtually excluded from CT-P13 entry, and those with severe disease were rare (8%) although the disease duration was long (18.5 years).
The profile of ADRs observed with CT-P13 was similar to that re-   (Figure 4b). These results could be a practical basis for switching to CT-P13 after treatment failure with other biologics.

TA B L E 4 Persistence of CT-P13 treatment and reasons for drug discontinuation
We conducted multivariable logistic regression analysis to explore the predictive factors of the response to CT-P13. We used absolute PASI <1 as the response criterion in the analysis instead of PASI response, which is commonly used, especially in clinical trials limited to moderate-to-severe psoriasis patients. It is not suitable for real-world studies involving less severe patients because PASI response varies greatly depending on the PASI score before the start of treatment. The multivariable analysis revealed four independent predictors of response to CT-P13. Male sex and psoriatic arthritis were significantly associated with a higher response rate, and BMI and use of topical steroids and/or vitamin D were associated with a poor response. These results generally corresponded to previous results of response to anti-TNF agents, including IFX.
De Simone et al. 30 reported that male sex, psoriatic arthritis, and baseline PASI ≤15 were three significant factors associated with the PASI 75 response by multivariable analysis. Naldi et al. 31 showed in an Italian nationwide cohort study that the proportion of patients who achieved PASI 75 was reduced with increased BMI. As well as efficacy, factor analyses were often performed on drug survival, and a recent meta-analysis reported that female sex and obesity pre-