Plain Language Summary

Inflammation causes psoriasis on the skin. Secukinumab is a drug that reduces inflammation. We studied how well secukinumab cleared psoriasis in 393 patients from North America and 990 patients not from North America. We also recorded whether side effects occurred with secukinumab. Secukinumab was given by injection for 5 weeks, then monthly for 1 year. After 12 weeks of secukinumab, 76.0% of patients from North America had skin that was clear or almost clear of psoriasis, 41.2% of patients from North America had skin that was clear of psoriasis, 66.2% of patients not from North America had skin that was clear or almost clear of psoriasis, and 28.1% of patients not from North America had skin that was clear of psoriasis. In both groups, skin remained clear from 12 weeks to 1 year of treatment. After 1 year of secukinumab, 67.7% of patients from North America had skin that was clear or almost clear of psoriasis, 39.8% of patients from North America had skin that was clear of psoriasis, 73.1% of patients not from North America had skin that was clear or almost clear of psoriasis, and 41.4% of patients not from North America had skin that was clear of psoriasis. Secukinumab also reduced discomfort from itching and pain. The most common side effects were common cold, upper respiratory infection, headache, diarrhea, and cough. Secukinumab completely or almost completely cleared the skin of many patients with psoriasis. Where they lived in the world did not affect skin clearance.

Introduction

Differences in demographic and disease characteristics between patients with psoriasis from different geographic regions and ethnic backgrounds have been suggested to impact the efficacy and safety of therapies [1,2,3,4,5,6]. For example, the typically lighter body weights of patients from Asia may impact response to treatment [7]. In addition, physicians should be aware that differences in the rates of comorbidities between patient groups could affect treatment decisions and outcomes. These differences could be of practical significance for clinicians and patients but may be obscured by the way in which data are reported in pivotal, often global, randomized, controlled, clinical trials, which do not delineate findings in this manner.

In 2013, the prevalence of psoriasis was estimated to be 7.4 million people in the USA [8]. Due to its chronic nature, psoriasis requires long-term management that incurs substantial costs. The estimated total annual cost of psoriasis was US $112 billion in the USA in 2013 [9] and CAN $1.7 billion in Canada in 2008 [10]. Furthermore, US patients with psoriasis are estimated to experience almost US $2000 in reduced productivity per year and a further US $2200 reduction in health-related quality of life compared with controls [11].

Despite the substantial physical and emotional burdens associated with psoriasis [12], many patients in the USA do not receive adequate treatment to control disease symptoms. Surveys conducted by the National Psoriasis Foundation in 2011 found that 23.6% of patients with moderate psoriasis and 9.4% of patients with severe psoriasis in the USA were not receiving treatment [13]. In addition, 52.3% of patients with psoriasis reported being dissatisfied with their treatment. The importance of clear skin cannot be overlooked because clinically important differences in quality of life are reported by people with clear skin compared with those with almost clear skin [14].

Secukinumab is a high-affinity, human IgG1κ monoclonal antibody that selectively binds to and neutralizes interleukin-17A. In phase 3 trials in psoriasis, secukinumab has been demonstrated to result in significantly greater skin clearance compared with placebo, etanercept, and ustekinumab, with a comparable safety profile [15,16,17,18]. In this post hoc analysis, data were pooled from four phase 3 trials to evaluate the safety and efficacy profile of secukinumab in North American (NA) and non-NA patients.

Methods

Data from 393 NA (USA and Canada) and 990 non-NA patients (Argentina, Australia, Belgium, Colombia, Egypt, Estonia, Finland, France, Germany, Guatemala, Hungary, Iceland, India, Israel, Italy, Japan, South Korea, Latvia, Lithuania, Mexico, The Philippines, Poland, Romania, Singapore, Spain, Sweden, Taiwan, and UK) with moderate to severe psoriasis were pooled from four phase 3, randomized, double-blind studies of secukinumab (Fig. 1). The included studies were ERASURE, FIXTURE, FEATURE, and JUNCTURE [15,16,17]. The article does not contain any new studies with human or animal subjects performed by any of the authors.

Fig. 1
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Composition of pooled study population by a phase 3 trial and b region. Sec secukinumab

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All studies had the following inclusion criteria: adults 18 years or older with chronic plaque-type psoriasis considered inadequately controlled by topical treatment, phototherapy, and/or previous systemic therapy, and who were diagnosed at least 6 months before randomization; baseline Psoriasis Area and Severity Index (PASI) score ≥12, Investigator’s Global Assessment (IGA) modified 2011 score ≥3, and total affected body surface area (BSA) ≥10%. Exclusion criteria included active ongoing inflammatory diseases; active, ongoing, chronic, or recurrent infectious disease, or evidence of tuberculosis infection; or an underlying condition significantly immunocompromising the patient and/or placing the patient at unacceptable risk for receiving immunomodulatory therapy [e.g., lymphoproliferative disease; malignancy; history of malignancy within the past 5 years; medical history of human immunodeficiency virus, hepatitis B, or hepatitis C].

Study Designs and Assessments

All patients received secukinumab (300 or 150 mg) at baseline, weeks 1, 2 and 3, then every 4 weeks from week 4 to 48. In all studies, the coprimary endpoints were 75% improvement from baseline in PASI score (PASI 75) and IGA modified 2011 (IGA mod 2011) [19] response of 0/1 (clear/almost clear) at week 12. Secondary endpoints included PASI 90 and PASI 100 response rates at week 12. Achievement of Dermatology Life Quality Index (DLQI) [20] score of 0/1, representing little or no effect of psoriasis on patient quality of life, was also measured at week 12. In ERASURE and FIXTURE, reduction in symptoms of itching, pain, and scaling as measured by Psoriasis Symptom Diary© (PSD) [21] at week 12 were key secondary endpoints.

Pooled Analysis Design and Statistical Methods

Data up to week 52 of the ERASURE, FIXTURE, FEATURE, and JUNCTURE studies were pooled. Missing values were handled by the multiple imputation method in which missing data are replaced by values derived from large datasets of possible values. The SAS multiple imputation procedure was used to generate datasets for 500 imputations. For comparison of response to secukinumab treatment between NA and non-NA population, the Cochran–Mantel–Haenszel test was used and adjusted for age (< 45 or ≥ 45 years), gender, study site, body weight, treatment group, previous systemic treatment (including oral and biologic), previous biologic treatment, and baseline PASI score (≤ 20 or > 20). Sensitivity analysis of the contribution of patient factors to efficacy was performed by logistic regression with study site, weight (< 90 or ≥ 90 kg), age, gender, body mass index (BMI), baseline PASI score, race (Caucasian or non-Caucasian), current smoking status, and treatment as explanatory variables. Factors predictive of secukinumab efficacy in the overall patient population were determined by first performing separate regression analyses including one of the following: current smoking status, race (Caucasian or non-Caucasian), gender, baseline BMI, and age in addition to NA and treatment as regressors. Multiple regression analysis was then performed for factors with P < 0.05 from the earlier analysis, all included together with study site, NA, and treatment as additional explanatory variables. All analyses were not prespecified and no adjustments were made for multiple comparisons. Safety data are presented for all patients who took at least one dose of study drug during the treatment period.

Results

Patients

Differences were observed in demographic and baseline characteristics between the NA and non-NA populations (Table 1). Notably, the secukinumab 300 and 150 mg NA populations, compared with the non-NA populations, had greater mean body weight (96.3–97.4 versus 82.5 kg; P < 0.001) and BMI (32.6–32.8 versus 28.1 kg/m2; P < 0.001). In the NA population, compared with the non-NA population, there were more White patients (83.2–83.8% versus 67.7–68.9%) and fewer Asian patients (5.8–7.4% versus 23.3–23.6%). The NA populations had a lower mean baseline PASI score (19.4–20.2 versus 23.8–24.0; P < 0.001) and less BSA affected (25.2–26.6% versus 35.9–36.3%; P < 0.001). Psoriatic arthritis was more common in the NA population (23.0–24.3%) than in the non-NA population (15.2–16.6%; P < 0.001). Differences were also observed in exposure rates to previous therapies for psoriasis between the NA and non-NA population: a lower proportion of NA patients was previously exposed to nonbiologic systemic psoriasis therapy (37.6–45.0% versus 60.7–61.3%; P < 0.001) and, similarly, fewer NA patients had previously failed a systemic psoriasis therapy (37.6–46.1% versus 50.9%; P < 0.001). However, significantly more NA patients than non-NA patients had been previously exposed to a biologic psoriasis therapy (45.5–52.9% versus 11.0–12.0%; P < 0.001).

Table 1 Patient demographics and baseline disease characteristics
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Efficacy

IGA mod 2011 and PASI responses peaked at week 16 and were sustained to week 52 in both NA and non-NA patients with both secukinumab 300 mg and secukinumab 150 mg (Figs. 2, 3, 4, 5, 6). At week 16, the greatest efficacy was observed with secukinumab 300 mg; PASI 90 and PASI 100 responses were achieved by 75.6% and 47.2% of NA patients, respectively. In comparison, PASI 90 and PASI 100 responses were achieved by 75.1% and 40.1% of non-NA patients, respectively. At week 16 with secukinumab 150 mg, PASI 90 and PASI 100 responses were achieved by 42.5% and 21.1% of NA patients, respectively, and by 62.1% and 26.5% of non-NA patients, respectively. Efficacy responses at week 12 and 52 are presented in Table 2.

Fig. 2
figure 2

Modified IGA responses of 0 or 1. n represents the number of evaluable subjects. Missing values were handled by multiple imputation. IGA mod 2011 Investigator’s Global Assessment, 2011 modified version

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Fig. 3
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Modified IGA responses of 0. n represents the number of evaluable subjects. Missing values were handled by multiple imputation. IGA mod 2011 Investigator’s Global Assessment, 2011 modified version

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Fig. 4
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PASI 75 responses. n represents the number of evaluable subjects. Missing values were handled by multiple imputation. PASI 75 75% improvement from baseline Psoriasis Area and Severity Index

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Fig. 5
figure 5

PASI 90 responses. n represents the number of evaluable subjects. Missing values were handled by multiple imputation. PASI 90 90% improvement from baseline Psoriasis Area and Severity Index

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Fig. 6
figure 6

PASI 100 responses. n represents the number of evaluable subjects. Missing values were handled by multiple imputation. PASI 100 100% improvement from baseline Psoriasis Area and Severity Index

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Table 2 Efficacy responses at week 12 and week 52
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Differences in efficacy between NA and non-NA patients were more pronounced with secukinumab 150 mg than with secukinumab 300 mg. For example, comparison of the difference in PASI 90 response rates at week 52 showed a greater difference between NA and non-NA patients with secukinumab 150 mg than with secukinumab 300 mg. From week 12 onward, non-NA patients consistently reported having greater skin clearance with secukinumab 150 mg than NA patients. Less variation was observed in efficacy responses between NA and non-NA patients with secukinumab 300 mg. At week 12, a trend toward better response in NA patients compared with non-NA patients was observed when adjusted for age (< 45 or ≥ 45 years), gender, study site, body weight, treatment group, previous systemic treatment (including oral and biologic), previous biologic treatment, and baseline PASI score (≤ 20 or > 20) (Table 3). Sensitivity analysis of the contribution of individual patient factors to efficacy at week 12 found BMI as the only factor with a consistently significant effect on efficacy across different efficacy measures in both NA and non-NA patients (Table 4). Separate regression analyses with each factor were performed to identify patient factors associated with secukinumab response at week 12 in the overall patient population. Patients factors identified as significant (P < 0.05) from these analyses were then subjected to multiple regression analysis to evaluate their ability to predict secukinumab response (Table 5). Across the different efficacy variables, BMI was the only factor found to be a consistently significant predictor of response to secukinumab. Interestingly, NA patients were significantly more likely to achieve complete psoriasis clearance as measured by IGA mod 2011 0 response [odds ratio (95% confidence interval), 1.84 (1.32–2.56); P = 0.0003] and PASI 100 response [odds ratio (95% confidence interval), 1.91 (1.33–2.73); P = 0.0004].

Table 3 Effect of geographical region on efficacy at week 12 for NA versus non-NA patients
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Table 4 Sensitivity analysis of contribution of patient factors to efficacy at week 12
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Table 5 Patient factors associated with secukinumab response at week 12
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The speed of response to secukinumab was rapid in both NA and non-NA patients, and the time to 50% reduction in mean PASI score was similar in both populations (Fig. 7). With secukinumab 300 mg, 50% reduction in mean PASI score was achieved in 2.9 weeks for both NA patients [95% confidence interval (CI) 2.7–3.1 weeks] and non-NA patients (95% CI 2.8–3.1 weeks). With secukinumab 150 mg, 50% reduction in mean PASI score was achieved in 3.7 weeks for both NA patients (95% CI 3.4–4.2 weeks) and non-NA patients (95% CI 3.5–3.9 weeks).

Fig. 7
figure 7

Mean percent change in PASI score over time. A repeated-measures, mixed-effects model was used to analyze the mean percent change from baseline in PASI score. The median time to 50% reduction in mean PASI score was estimated from parametric bootstrap samples with use of linear interpolation between time points. CI confidence interval, NA North American, PASI Psoriasis Area Severity Index

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Secukinumab was also observed to improve patient quality of life in both NA and non-NA patients. At week 12, DLQI responses of 0/1 were similar between NA patients (60.7% with secukinumab 300 mg and 45.5% with secukinumab 150 mg) and non-NA patients (58.8% with secukinumab 300 mg and 51.8% with secukinumab 150 mg; Table 6). These responses were maintained to week 52 in both NA patients (64.6% with secukinumab 300 mg and 44.2% with secukinumab 150 mg) and non-NA patients (69.2% with secukinumab 300 mg and 57.3% with secukinumab 150 mg). Improvement in patient-reported symptoms of itching, pain, and scaling was observed after 12 weeks of treatment with secukinumab in both NA and non-NA patients (Fig. 8). A similar proportion of NA and non-NA patients showed improvement in these symptoms with secukinumab 150 mg, and, interestingly, there was a trend for greater response with secukinumab 300 mg in NA patients than in non-NA patients, especially for pain and scaling.

Table 6 DLQI mean score and response at week 12 and week 52
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Fig. 8
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Improvement in patient-reported symptoms of itching, pain, and scaling at week 12. The Psoriasis Symptom Diary was conducted only in ERASURE and FIXTURE. Improvement in symptoms was defined as a prespecified point improvement at week 12 of 2.2, 2.2, and 2.3 for symptoms of psoriasis-related itching, psoriasis-related pain, and psoriasis-related scaling, respectively. NA North American

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Safety

Secukinumab demonstrated a good and comparable safety profile in both the NA and non-NA populations (Table 7). Overall rates of adverse events (AEs) and serious AEs were similar between the two populations. Nasopharyngitis was the most common AE and occurred at a numerically greater rate in the non-NA population (33.1–35.5 events per 100 patient-years) than in the NA population (22.7–24.3 events per 100 patient-years). Upper respiratory tract infection was the second most common AE in the NA population and occurred at a numerically greater rate than in the non-NA population (15.9–23.9 versus 5.8–6.2 events per 100 patient-years). No serious Candida infections were reported in either population, and all cases of candidiasis resolved on their own or with standard treatment and did not lead to discontinuation of secukinumab. Rates of discontinuation due to AEs were similar between the NA (4.5–5.2%) and non-NA (2.5–3.0%) populations.

Table 7 Adverse events in the North American and non-North American subgroups
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Discussion

Secukinumab demonstrated fast, robust, and sustained disease clearance with a good and comparable safety profile for both NA and non-NA patients with moderate to severe psoriasis. The efficacy profiles of secukinumab to week 52 in NA and non-NA patients remained similar to previous results from the overall populations [15, 22]. Furthermore, the efficacy of secukinumab between NA and non-NA patients was similar despite differences in baseline characteristics between the two populations. For example, patients from NA were heavier, had greater BMI, and were more likely to have psoriatic arthritis. Patients from NA were also more likely to have been previously exposed to biologic therapy, but no significant differences in the rates of biologic failure were reported between the groups. Differences were also observed in the racial composition of the two populations. Although both NA and non-NA populations were predominately White, the NA population had a greater number of White patients and fewer Asian patients compared with the non-NA population. The non-NA population had more severe disease as indicated by greater PASI and IGA mod 2011 scores and BSA affected at baseline. It is important to note that these variations could obscure differences in responses between NA and non-NA patients.

In both the NA and non-NA populations, improvements in disease clearance were observed at week 1 and 50% reduction in mean PASI score was achieved after 2.9 weeks of treatment with secukinumab 300 mg and 3.7 weeks of treatment with secukinumab 150 mg. The response to secukinumab peaked at week 16 and was maintained to week 52. Interestingly, non-NA patients receiving secukinumab 150 mg tended to achieve greater efficacy responses than NA patients receiving this dose. These differences were most pronounced with PASI 75 and PASI 90 assessments, and separation began at approximately week 12. The trend of lower responses between NA and non-NA patients with secukinumab 150 mg was not observed with secukinumab 300 mg. This finding suggests that the therapeutic benefit of secukinumab is not being maximized with the 150-mg dose. The greater response to secukinumab 150 mg in non-NA patients may be due to their lower body weight and/or greater disease severity at baseline. Responses to secukinumab 300 mg were more consistent between NA and non-NA patients to week 52. Overall, secukinumab 300 mg provided greater and more rapid efficacy than secukinumab 150 mg for both populations. At week 12, a trend toward greater response in NA patients was observed when adjusted for study site, body weight, treatment group, previous systemic treatment (including oral and biologic), previous biologic treatment, and baseline PASI score (≤ 20 or > 20). BMI had a significant effect on efficacy at week 12 in both NA and non-NA patients and was a predictor of lower efficacy in the overall patient population at week 12. However, these findings might not be surprising, as it has been reported that higher weight can decrease the efficacy of biologics in patients with psoriasis [23]. NA geographical residence was a predictor of achieving total psoriasis clearance at week 12, but evaluation of efficacy responses over time showed that NA and non-NA patients had smaller differences in response at later time points, especially for secukinumab 300 mg.

Improvements in baseline DLQI score at week 12 in both NA and non-NA patients were sufficient to meet the threshold (total DLQI score change ≥ 5) required for a minimal clinically important difference in patients with psoriasis receiving biologic therapy [24]. These findings, and patient-reported improvements in symptoms of itching, pain, and scaling, indicate that secukinumab improved the quality of life of both NA and non-NA patients.

The safety profile of secukinumab was similar in both the NA and non-NA populations. Nasopharyngitis and upper respiratory tract infection were the two most common adverse events, with nasopharyngitis being more common in the non-NA population and upper respiratory tract infection being more common in the NA population. No specific safety observations were made based on geographic region.

Limitations of this study include that it was a post hoc analysis.

Conclusions

This study of pooled results from four phase 3 trials demonstrates that treatment with secukinumab for moderate to severe psoriasis provides high efficacy, regardless of geographic regions, and a similar safety profile across geographic regions.