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Keywords:

  • biologics;
  • interleukin-12/23p40;
  • Japanese;
  • psoriasis;
  • ustekinumab

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

This phase 2/3, double-blind, placebo-controlled study was designed to assess the safety and efficacy of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis. Overall, 158 patients were randomized to receive ustekinumab 45 or 90 mg at weeks 0, 4, and every 12 weeks, or placebo with cross-over to ustekinumab at week 12. The primary end-point was the proportion of patients achieving at least 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 12. Physician’s Global Assessment (PGA), Dermatology Life Quality Index (DLQI), Nail Psoriasis Severity Index and joint pain Visual Analog Scale (VAS) were also measured. At week 12, 59.4% and 67.7% of ustekinumab 45 and 90 mg patients achieved PASI 75, respectively, compared with 6.5% in the placebo group (P < 0.0001 each). PASI 75 responses were maintained through week 64 in 65.0% and 78.6% of the ustekinumab-treated patients, respectively. Placebo cross-over patients had similar responses to ustekinumab-treated patients. Significant improvements in PGA, DLQI and VAS scores were observed at week 12 and generally maintained over time. Adverse events during the placebo-controlled period were similar among groups (45 mg, 65.6%; 90 mg, 59.7%; placebo, 65.6%). Serious adverse events were observed in 0%, 4.8% and 6.3% of patients, respectively. Through week 72, similar rates and types of adverse events and serious adverse events were reported in patients receiving 45 and 90 mg. Rates of injection site reactions and antibodies to ustekinumab were low. Ustekinumab was efficacious and generally well-tolerated in Japanese patients with moderate-to-severe plaque-type psoriasis through 72 weeks. These results are consistent with those reported in the global, phase 3 studies.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

Psoriasis is a chronic, immune-mediated skin disorder, with the prevalence varying among different ethnic populations.1 Psoriasis affects approximately 1–3% of the world’s population,2 but in Asian populations the estimated prevalence is between 0.05% and 0.3%.3,4 According to a survey of Japanese patients with psoriasis, 86% of patients had plaque psoriasis, with approximately 50% having moderate-to-severe disease.5 The prevalence of psoriasis in Japanese men (65.8%) is nearly twice that reported in Japanese women (34.2%).5

In Japan, patients with moderate-to-severe psoriasis are often treated with topical agents and/or phototherapy (psoralen ultraviolet A therapy and narrow-band ultraviolet B), which can have possible limited long-term efficacy and potentially an increased risk of skin cancers. Traditional systemic therapies for the treatment of psoriasis, including methotrexate,6 which is not approved to treat psoriasis in Japan,7 cyclosporin6 and etretinate8 can be limited in their use by potential adverse events, treatment failure and patient dissatisfaction.9,10 Recently, biologics have emerged as additional treatment options for patients with moderate-to-severe psoriasis; however, data for only anti-tumor necrosis factor (TNF)-α agents, including infliximab and adalimumab, exist for Japanese patients with psoriasis.11,12

Interleukin (IL)-12 and IL-23 are cytokines known to play an important role in the pathogenesis of psoriasis.13 In patients with psoriasis, IL-12 is important in the development of T-helper cell (Th)1 responses14 and IL-23 with Th17 immune responses.15,16 IL-12 and IL-23 are heterodimers with a common p40 subunit. The binding of the subunits to their respective receptors results in activation of specific intracellular signaling cascades.17,18

Ustekinumab (Stelara®; Janssen Biotech, Inc., Horsham, PA, USA) is a novel human, monoclonal antibody that binds the shared p40 subunit of IL-12 and IL-23 and prevents the cytokines from binding their respective receptors, thus blocking the downstream signaling cascades. The efficacy and safety of ustekinumab have been previously evaluated in North American and European patients with moderate-to-severe plaque-type psoriasis in one phase 219 and three phase 3 clinical trials,20–22 including the first head-to-head comparator trial of biologics for psoriasis (ustekinumab vs etanercept).22 Recently, the efficacy and safety of ustekinumab in Japanese patients with psoriasis had been suggested in a phase 1 clinical trial (Dr Osamu Nemoto, unpubl. data, 2007). In the current study, the efficacy of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis was evaluated for up to 64 weeks and safety was assessed for up to 72 weeks.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

Patients

This multicenter, phase 2/3, randomized, double-blind, placebo-controlled trial was conducted at 35 sites in Japan between March 2008 and March 2010. Patients eligible to participate in the study were at least 20 years of age, were diagnosed with moderate-to-severe plaque-type psoriasis at least 6 months prior to study entry, at least 10% body surface area involvement, had baseline Psoriasis Area and Severity Index (PASI) score of 12 or higher, were candidates for phototherapy or systemic psoriasis therapy, were using contraceptives to prevent pregnancy, and agreed not to receive the bacillus Calmette–Guérin vaccine during the study and for 1 year after final treatment.

Patients ineligible to participate in the study had non-plaque forms of psoriasis; had an onset of psoriasis or aggravation of symptoms due to treatment with beta-blockers, calcium antagonists, or lithium products; had other active skin diseases; had received systemic therapies or phototherapies within the previous 4 weeks, or topical therapies within the previous 2 weeks; or had opportunistic infection, serious infection or malignancy. Patients with a history of active or latent tuberculosis (TB) were excluded. However, patients with latent TB diagnosed during screening could be treated with an anti-TB agent (i.e. isoniazid [INH]) for at least 3 weeks prior to randomization. This study was conducted in accordance with the guideline for Good Clinical Practice, conforms to the provisions of the Declaration of Helsinki, and all patients provided written informed consent.

Study design

This study consisted of a placebo-controlled period (weeks 0–12), an active treatment period (weeks 12–64) and a follow-up period (weeks 64–72) (Fig. 1). At baseline, 158 patients were randomly assigned to receive ustekinumab 45 mg (n = 64), ustekinumab 90 mg (n = 62) or placebo (n = 32). Patients were randomized (2:2:1) to receive ustekinumab 45 or 90 mg by s.c. injection at weeks 0, 4, and every 12 weeks, or placebo at weeks 0 and 4, with a cross-over to ustekinumab 45 or 90 mg at week 12, and treatment at weeks 16, 28, 40 and 52. At week 28, patients with less than 50% improvement in PASI discontinued the study agent.

image

Figure 1.  Study design.

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Study assessments

Efficacy parameters were analyzed through week 64 and safety parameters, through week 72.

The PASI score, which measures the severity of psoriasis, ranges from a score of 0 (no psoriasis) to 72 (very severe).23 The Physician’s Global Assessment (PGA) of a patient’s psoriasis is a score designated as cleared (0), minimal (1), mild (2), marked (3) or severe (4). The Dermatology Life Quality Index (DLQI) is a 10-item patient-reported questionnaire measuring the effect of psoriasis on six different aspects of patients’ quality of life, with total scores ranging from 0 (not at all) to 30 (very much).24 A DLQI score of 0 or 1 indicates no negative impact on quality of life, while a score of more than 10 represents a very large impact on quality of life.25 The Nail Psoriasis Severity Index (NAPSI) is determined using a target nail representing the most severe nail psoriasis at baseline. The nail is divided into quadrants that were graded for four characteristics of both nail matrix psoriasis and nail bed psoriasis, with a highest possible total score of 8.26 The Visual Analog Scale (VAS) measures patient-assessed joint pain, with 0 indicating no pain and 100 indicating the worst pain. The patient-reported 36-item Short Form Health Survey (SF-36) measures eight health domains and consists of physical component summary and mental component summary scores.27 A clinically meaningful improvement in SF-36 is indicated by an increase in score of at least 5 points.28 The Psoriasis Disability Index (PDI) is a disease-specific assessment of the effect of psoriasis on patients’ quality of life,29 with a higher score denoting a greater impact on the quality of life.

The primary end-point of this study was the proportion of patients achieving at least a 75% improvement in PASI (PASI 75) at week 12. Major secondary end-points included the proportion of patients with a PGA score of 0 (cleared) or 1 (minimal) at week 12 and the change in DLQI from baseline to week 12. Other secondary end-points included improvement from baseline to weeks 12 through 64 in nail psoriasis (in patients who had psoriatic nails at baseline), as assessed by NAPSI, and joint pain (in patients with joint pain at baseline), as measured by the change in VAS.

Statistical analyses

Efficacy analyses were based on all randomized patients with efficacy data after randomization, and patients were included in safety summaries based on actual treatment received.

As mentioned previously, the primary end-point was the proportion of patients achieving a PASI 75 score at week 12. From the results of previous clinical studies, PASI 75 response rates in the placebo group, ustekinumab 45 and 90 mg groups were estimated to be 10%, 60% and 70%, respectively. The sample size of 50 patients in each ustekinumab group and 25 patients in the placebo group were planned to provide 90% statistical power to detect a difference in the primary end-point at a two-sided overall significance level of 0.05 using Holm’s method.30

The primary efficacy end-point and the proportion of patients with a PGA score of cleared (0) or minimal (1) at week 12 were compared between the treatment groups (45 mg vs placebo and 90 mg vs placebo) using Fisher’s exact test. The change in DLQI from baseline to week 12 was compared between the treatment groups, using the two-sample Student’s t-test. To maintain an overall type I error rate of 0.05, Holm’s procedure was used for multiple treatment arm comparisons within each efficacy end-point described above.

Patients who discontinued the study treatment because of an unsatisfactory therapeutic effect or initiated prohibited medications were considered as treatment failures. These patients were classified as not having achieved the response for binary variables and had baseline values carried forward for continuous variables after they met the treatment failure criteria. No imputation was performed after the treatment failure criteria were applied, except for the dichotomous end-points such as PASI 75 and PGA response rates at week 12, which were assigned as not achieving the respective endpoints.

Safety data analyses and data presentation

Safety was assessed by adverse event reporting throughout the study and through laboratory tests (e.g. hematology, urinalysis) and physical examination. Adverse events were coded using the Medical Dictionary for Regulatory Activities Japanese Edition.31 Treatment-emergent adverse events, serious adverse events, and adverse events leading to discontinuation were summarized by system organ class and preferred term for each treatment group. No formal statistical testing for the incidence of adverse events was performed.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

Baseline patient demographics and disease characteristics

Of the 193 patients screened, 160 patients were randomized and 158 patients were treated with placebo (n = 32), ustekinumab 45 mg (n = 64) or ustekinumab 90 mg (n = 62) (Fig. 2). The primary population for the efficacy analysis consisted of 157 patients, as one patient was excluded due to lack of any efficacy data after receiving a single dose of placebo. Baseline patient demographics and disease characteristics were comparable among treatment groups. The median age of patients was 46.0 years, 80.3% were men, the mean weight was 72.0 ± 14.0 kg, the mean body mass index was 25.8 ± 4.3, and the mean duration of psoriasis was approximately 16 years (Table 1). The mean extent of body surface area involvement was approximately 47%, and the mean PASI score was approximately 29. At baseline, 13.3% (21/158) of all patients were diagnosed as having latent TB at screening. A large proportion of patients (64.6%, 102/158) had nail psoriasis, with substantial nail involvement (mean NAPSI score of 4.0 ± 2.0). At baseline, 22 patients reported joint pain, with a mean VAS score of 47.0 ± 24.6. Of note, 14 patients in this study had a history of psoriatic arthritis (PsA). However, two of these 14 patients did not report joint pain at baseline and, therefore, VAS scores were reported for only 12 of the patients with PsA. All patients (100%) had been previously treated with topical agents, while similar proportions of patients had used either phototherapy (67.7%, 107/158) or systemic agents (75.9%, 120/158) (Table 1).

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Figure 2.  Study flow and patient disposition.

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Table 1.   Baseline demographics and disease characteristics
 PlaceboUstekinumab 45 mgUstekinumab 90 mgTotal
  1. Phototherapy includes psoralen and ultraviolet A therapy, ultraviolet (UV)-A and narrow-band UV-B. NAPSI, Nail Psoriasis Severity Index; SD, standard deviation; VAS, Visual Analog Scale.

Treated patients, n326462158
Median age, years49.045.044.0 46.0
Men, n (%)26 (83.9)53 (82.8)47 (75.8)126 (80.3)
Weight (kg), mean ± SD71.2 ± 10.973.2 ± 15.471.1 ± 14.0 72.0 ± 14.0
Body mass index
 Mean ± SD25.3 ± 4.026.1 ± 4.425.7 ± 4.3 25.8 ± 4.3
 <25, n (%)15 (48.4)26 (40.6)30 (48.4) 71 (45.2)
 ≥25, n (%)16 (51.6)38 (59.4)32 (51.6) 86 (54.8)
Duration of psoriasis, years, mean ± SD16.0 ± 11.215.8 ± 8.217.3 ± 10.7 16.4 ± 9.8
Involved body surface area (%), mean ± SD49.8 ± 22.547.0 ± 23.746.6 ± 19.7 47.4 ± 21.8
Psoriasis Area and Severity Index score (0–72), mean ± SD30.3 ± 11.830.1 ± 12.928.7 ± 11.2 29.6 ± 12.0
 <20, n (%) 6 (18.8)16 (25.0)13 (21.0) 29 (23.0)
 ≥20, n (%)26 (81.3)48 (75.0)49 (79.0) 97 (77.0)
Physician’s Global Assessment, mean ± SD 3.4 ± 0.6 3.5 ± 0.6 3.5 ± 0.8  3.5 ± 0.7
 Cleared (0), n (%) 0 (0.0) 0 (0.0) 0 (0.0)  0 (0.0)
 Minimal (1), n (%) 0 (0.0) 0 (0.0) 0 (0.0)  0 (0.0)
Dermatology Life Quality Index, mean ± SD10.5 ± 6.211.4 ± 6.510.7 ± 6.4 10.9 ± 6.4
 <10, n (%)16 (50.0)30 (46.9)32 (51.6) 78 (49.4)
 ≥10, n (%)16 (50.0)34 (53.1)30 (48.4) 80 (50.6)
Patients with psoriatic arthritis, n (%) 1 (3.1) 6 (9.4) 7 (11.3) 14 (8.9)
Patients with latent tuberculosis, n (%) 7 (21.9) 9 (14.1) 5 (8.1) 21 (13.3)
NAPSI, if nail psoriasis present
 Patients, n184440102
 Mean ± SD 4.6 ± 2.5 3.7 ± 1.8 4.1 ± 2.0  4.0 ± 2.0
VAS, in patients with joint pain at baseline
 Patients, n 3 6 13 22
 Mean ± SD44.0 ± 26.956.8 ± 25.243.2 ± 24.6 47.0 ± 24.6
Prior medications and exposure, n (%)
 Topical agents32 (100.0)64 (100.0)62 (100.0)158 (100.0)
 Phototherapy20 (62.5)36 (56.3)51 (82.3)107 (67.7)
 Systemic agents21 (65.6)47 (73.4)52 (83.9)120 (75.9)
  Cyclosporin17 (53.1)33 (51.6)34 (54.8) 84 (53.2)
  Etretinate13 (40.6)27 (42.2)27 (43.5) 67 (42.4)
  Methotrexate 3 (9.4) 3 (4.7)10 (16.1) 16 (10.1)
  Oral and injectable steroids 2 (6.3) 3 (4.7) 4 (6.5)  9 (5.7)
  Chinese herbal medicines 2 (6.3) 8 (12.5)11 (17.7) 21 (13.3)
  Vitamin A products 0 (0.0) 0 (0.0) 1 (1.6)  1 (0.6)
  Anti-rheumatic drug 2 (6.3) 1 (1.6) 3 (4.8)  6 (3.8)
  Biotin products 0 (0.0) 0 (0.0) 3 (4.8)  3 (1.9)
  Biologics 0 (0.0) 1 (1.6) 0 (0.0)  1 (0.6)
  Other 0 (0.0) 1 (1.6) 2 (3.2)  3 (1.9)

Efficacy

Through week 12

At week 12, 59.4% (38/64) of patients receiving ustekinumab 45 mg and 67.7% (42/62) of patients receiving ustekinumab 90 mg achieved a PASI 75 response (primary end-point), compared with 6.5% (2/31) of those receiving placebo (P < 0.0001 for both; Table 2). A greater median improvement in PASI score from baseline through week 12 was observed in patients treated with ustekinumab 45 mg (84.2%) and 90 mg (84.7%) compared with those treated with placebo (0.0%). Additionally, 82.8% (53/64) of patients receiving ustekinumab 45 mg and 83.9% (52/62) of patients receiving ustekinumab 90 mg achieved at least a 50% improvement in PASI (PASI 50) compared with 12.9% (4/31) receiving placebo (P < 0.0001 for both). Similarly, a greater proportion of patients receiving ustekinumab 45 mg (21/64, 32.8%; P = 0.0013) and ustekinumab 90 mg (27/62, 43.5%; P < 0.001) achieved a 90% improvement in PASI (PASI 90) from baseline compared with receiving placebo (1/31, 3.2%; Table 2).

Table 2.   Clinical responses during the placebo-controlled period (from baseline through week 12)
 PlaceboUstekinumab 45 mgP-value vs placeboUstekinumab 90 mgP-value vs placebo
  1. One patient was randomized but did not receive active treatment and is not included in the efficacy analyses. N/A, not applicable; NAPSI, Nail Psoriasis Severity Index; PASI, Psoriasis Area and Severity Index; PASI 50, 75, 90, at least 50%, 75%, 90% improvement in PASI score from baseline, respectively 50% improvement in PASI score from baseline; PGA, Physician’s Global Assessment; SD, standard deviation; VAS, Visual Analog Scale.

Improvement in PASI score, n (%)
 n31 64  62 
 PASI 50 4 (12.9) 53 (82.8)<0.0001 52 (83.9)<0.0001
 PASI 75 2 (6.5) 38 (59.4)<0.0001 42 (67.7)<0.0001
 PASI 90 1 (3.2) 21 (32.8)0.0013 27 (43.5)<0.0001
Percent improvement in PASI score
 n30 62  61 
 Mean ± SD10.9 ± 31.7 73.1 ± 29.6<0.0001 75.0 ± 29.0<0.0001
 Median 0.0 84.2  84.7 
Proportion of patients with PGA scores of 0 or 1
 n (%) 3 (9.7) 37 (57.8)<0.0001 43 (69.4)<0.0001
Improvement in NAPSI score
 n17 43  40 
 Mean ± SD−2.9 ± 27.8  7.7 ± 95.10.6541 10.0 ± 66.10.4395
 Median 0.0  0.0  20.0 
Improvement in VAS score
 n 3  6  13 
 Mean ± SD 8.0 ± 13.0−38.5 ± 28.9N/A−9.3 ± 18.2N/A
 Median 1.0−41.0 −10.0 

A significantly greater proportion of ustekinumab-treated patients (45 mg, 37/64, 57.8%; 90 mg, 43/62, 69.4%) had a PGA score of cleared (0) or minimal (1) at week 12 compared with placebo-treated patients (3/31, 9.7%; P < 0.0001 for both; Table 2). At week 12, the mean improvement in NAPSI was 7.7 ± 95.1 and 10.0 ± 66.1 in the ustekinumab 45 mg and 90 mg groups, respectively (Table 2). The mean change in joint pain (in patients with baseline joint symptoms) from baseline to week 12 using VAS was −38.5 ± 28.9 (45 mg group) and −9.3 ± 18.2 (90 mg group) (Table 2).

Consistent with clinical assessments, improvements were also reported in patient-reported outcomes (Table 3). Mean improvements in DLQI score from baseline to week 12 were −8.0 ± 6.5 in the ustekinumab 45 mg group and −7.4 ± 6.5 in the 90 mg group, compared with −0.3 ± 5.3 in the placebo group (P < 0.001 for each). A greater proportion of patients receiving ustekinumab (45 mg, 30.6%; 90 mg, 32.8%) achieved DLQI scores of 0 or 1 at week 12 compared with placebo (6.7%). Improvements in the physical components of the SF-36 score were greater in the ustekinumab 45 mg group (7.8 ± 14.5; P = 0.0033) and 90 mg group (5.1 ± 12.0; P = 0.0164) than in the placebo group (−0.95 ± 9.6), with a clinically meaningful improvement (increase of at least 5 points) reported in ustekinumab-treated patients. Similarly, some improvements were reported for the mental components of the SF-36 through week 12 (P = 0.1006 for 45 mg vs placebo, P = 0.0742 for 90 mg vs placebo; Table 3). Mean improvements in PDI from baseline at week 12 were also greater in patients receiving ustekinumab (45 mg, −8.6 ± 9.6; 90 mg, −12.0 ± 11.8) than in those receiving placebo (0.1 ± 4.2) (P < 0.0001 for each).

Table 3.   Health-related quality of life parameters (from baseline through weeks 12 and 64)
 Week 12Week 64
PlaceboUstekinumab 45 mgUstekinumab 90 mgUstekinumab 45 mgUstekinumab 90 mg
  1. Does not include placebo cross-over patients. One patient was randomized but did not receive active treatment and is not included in the efficacy analyses. DLQI, Dermatology Life Quality Index; PDI, Psoriasis Disability Index; SD, standard deviation; SF-36, 36-item Short Form Health Survey.

n3162616056
Improvement in DLQI score
 Mean ± SD−0.3 ± 5.3−8.0 ± 6.5−7.4 ± 6.5−7.4 ± 6.9−7.9 ± 6.4
 Median0.0−7.0−6.0−5.0−6.0
DLQI score of 0 or 1, n (%) 1 (6.7)19 (30.6)20 (32.8)23 (38.3)20 (35.7)
Change in SF-36 scores
 Physical component summary score
  n3162616056
  Mean ± SD−0.95 ± 9.67.8 ± 14.55.1 ± 12.08.3 ± 15.56.7 ± 13.0
  Median0.02.82.54.14.4
 Mental component summary score
  n3162616056
  Mean ± SD2.0 ± 6.85.3 ± 9.85.8 ± 10.55.1 ± 10.56.9 ± 9.4
  Median0.04.14.73.95.9
Change in PDI total score
 n3162616056
 Mean ± SD0.1 ± 4.2−8.6 ± 9.6−12.0 ± 11.8−10.7 ± 9.7−14.3 ± 10.2
 Median0.0−6.5−9.0−10.0−12.0
Through week 64

Psoriasis Area and Severity Index 75 response rates continued to increase after week 12 and were generally maintained through week 64 (Fig. 3a). From week 28 (45 mg, 44/64, 68.8%; 90 mg, 42/59, 71.2%) through week 64 (45 mg, 39/60, 65.0%; 90 mg, 44/56, 78.6%), a consistent PASI 75 response was observed in the ustekinumab-treated patients (Fig. 3a). Patients receiving placebo crossed over to ustekinumab at week 12 and subsequently had response rates similar to patients originally randomized to receive ustekinumab at baseline.

image

Figure 3.  (a) Proportion of patients achieving at least a 75% improvement in Psoriasis Area and Severity Index (PASI 75) response from baseline to week 64, (b) a PASI 90 response from baseline to week 64 and (c) the median percent improvement in PASI from baseline to week 64.

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Psoriasis Area and Severity Index 90 responses were achieved by 42.2% (27/64) and 57.6% (34/59) of patients in the ustekinumab 45 and 90 mg groups, respectively, at week 28 (Fig. 3b). At week 64, approximately one-half of all ustekinumab-treated patients had achieved a PASI 90 response (45 mg, 30/60, 50%; 90 mg, 31/56, 55.4%) and 91.7% (55/60) and 89.3% (50/56), respectively, achieved a PASI 50 response (data not shown). Placebo cross-over patients had response rates similar to those in patients initially treated with ustekinumab.

Median percent improvements in PASI over time were comparable among ustekinumab-treated patients and were maintained through 64 weeks (Fig. 3c). At week 64, a median improvement in PASI of approximately 90% was reported in all ustekinumab-treated patients. Two ustekinumab-treated patients achieving PASI 90 responses are shown in Figure 4. Improvements in PASI scores are evident over time in both ustekinumab-treated patients. Ten patients (6.4%) developed antibodies against ustekinumab during the study period, and the proportion of these patients achieving PASI responses was slightly lower than those without antibodies (data not shown).

image

Figure 4.  Two ustekinumab-treated patients achieving at least a 90% improvement in Psoriasis Area and Severity Index (PASI 90) from baseline to week 64.

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At week 64, the mean improvement in NAPSI score was 56.6 ± 43.2% and 67.8 ± 37.5% for the ustekinumab 45 and 90 mg groups, respectively. The mean change in joint pain VAS at week 64 was −35.3 ± 38.6 in the ustekinumab 45 mg and −27.2 ± 28.4 in the 90 mg group, showing continued improvement over time (data not shown).

Mean improvements in DLQI score from baseline to week 64 in ustekinumab-treated patients were comparable between groups (45 mg, −7.4 ± 6.9; 90 mg, −7.9 ± 6.4) and similar to those observed at week 12 (Table 3). At week 64, the mean change in the physical components of the SF-36 score was 8.3 ± 15.5 in the ustekinumab 45 mg group and 6.7 ± 13.0 in the 90 mg group, consistent with a clinically meaningful improvement.28,32 Improvements in the mental components of the SF-36 were maintained through week 64 (Table 3). Mean improvements in PDI at week 64 (45 mg, −10.7 ± 9.7; 90 mg, −14.3 ± 10.2) were also similar to improvements reported at week 12.

Safety

Through week 12

During the placebo-controlled period, most adverse events were mild and did not result in discontinuation of treatment. The proportion of patients reporting at least one adverse event was comparable among ustekinumab (45 mg, 42/64, 65.6%; 90 mg, 37/62, 59.7%) and placebo (21/32, 65.6%) groups (Table 4). The most commonly reported adverse event in the placebo group through week 12 was exacerbation of psoriasis (8/32, 25.0%). The most commonly reported adverse event in the ustekinumab-treated patients was nasopharyngitis (45 mg, 10/64, 15.6%; 90 mg, 10/62, 16.1%). Increased blood triglycerides were reported in 3.1%, 10.9% and 0.0% of patients treated with placebo, ustekinumab 45 and 90 mg, respectively, without evidence of a dose response. Overall, 6.3% (2/32) of placebo-treated patients, 0.0% (0/64) of ustekinumab 45 mg patients and 6.5% (4/62) of ustekinumab 90 mg patients discontinued the study agent due to adverse events (Table 4).

Table 4.   Adverse events through week 72
 Weeks 0–12Weeks 0–72
PlaceboUstekinumab 45 mgUstekinumab 90 mgUstekinumab 45 mgUstekinumab 90 mg
  1. Patients who experienced adverse events while receiving placebo (weeks 0–12) are included in the “Weeks 0–72” cumulative column, based on their initial randomization group (placebo to 45 mg or placebo to 90 mg). Placebo-treated patients who never received ustekinumab (n = 4) were excluded from the 0–72 week analyses. Common adverse events were those occurring in at least 10% of patients in any treatment group. §Non-cutaneous malignancies included one case of prostate cancer in the 90 mg group reported during the placebo-controlled period and one case of cervical carcinoma in situ in the 45 mg group reported after week 28. Includes all serious adverse events in the Medical Dictionary for Regulatory Activities Japanese Edition cardiovascular and neurological system organ class and included one case of congestive heart failure in the placebo group and one case of cerebral hemorrhage in the 90 mg group after week 28. NMSC, non-melanoma skin cancer (includes basal cell and squamous cell carcinomas).

n3264627975
Mean duration of follow-up, weeks11.511.811.769.168.0
Patients with one or more adverse events, n (%)21 (65.6)42 (65.6)37 (59.7)76 (96.2)74 (98.7)
Common adverse events, n (%)
 Nasopharyngitis 3 (9.4)10 (15.6)10 (16.1)44 (55.7)41 (54.7)
 Increased blood triglycerides 1 (3.1) 7 (10.9) 0 (0.0)18 (22.8)10 (13.3)
 Increased blood creatine phosphokinase 1 (3.1) 1 (1.6) 0 (0.0)13 (16.5)14 (18.7)
 Seasonal allergy 0 (0.0) 0 (0.0) 0 (0.0) 9 (11.4)12 (16.0)
 Increased alanine aminotransferase 1 (3.1) 1 (1.6) 1 (1.6) 6 (7.6) 9 (12.0)
 Tinea pedis 0 (0.0) 0 (0.0) 0 (0.0) 2 (2.5) 8 (10.7)
 Psoriasis 8 (25.0) 1 (1.6) 3 (4.8) 3 (3.8) 5 (6.7)
Adverse events leading to withdrawal of study agent, n (%) 2 (6.3) 0 (0.0) 4 (6.5) 1 (1.3) 5 (6.7)
Serious adverse events, n (%) 2 (6.3) 0 (0.0) 3 (4.8) 6 (7.6) 7 (9.3)
Adverse events of special interest, n (%)
 Infections 6 (18.8)13 (20.3)15 (24.2)51 (64.6)55 (73.3)
 Serious infections 0 (0.0) 0 (0.0) 1 (1.6) 2 (2.5) 1 (1.3)
 Malignancies 0 (0.0) 0 (0.0) 1 (1.6) 1 (1.3) 1 (1.3)
  NMSC 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
  Non-cutaneous§ 0 (0.0) 0 (0.0) 1 (1.6) 1 (1.3) 1 (1.3)
 Serious cardiac and neurological events 1 (3.1) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.3)

The proportion of patients reporting serious adverse events through week 12 was low (placebo, 2/32, 6.3%; ustekinumab 45 mg, 0/64, 0.0%; ustekinumab 90 mg, 3/62, 4.8%). Infections were reported in 18.8%, 20.3% and 24.2% of patients in the placebo, 45 and 90 mg groups, respectively. Only one serious infection (pneumonia) was reported during the placebo-controlled period (ustekinumab 90 mg group) (Table 4). The patient was hospitalized twice with a diagnosis of pneumonia and treated with antibiotics. Peripheral and pulmonary eosinophilias were noted during the evaluation, but no definitive etiology was identified. Through week 12, one case of prostate cancer was reported in the ustekinumab 90 mg group. During the placebo-controlled period, one case of non-ischemic congestive heart failure was reported in a patient in the placebo group. No cardiovascular deaths, myocardial infarctions or strokes were reported during this initial period (Table 4).

Through week 72

Safety data were collected through 72 weeks. The most commonly reported adverse events through week 72 included nasopharyngitis, increased blood triglycerides and creatine phosphokinase, and seasonal allergies, including allergic rhinitis (Table 4). The proportion of patients reporting at least one adverse event was comparable between patients receiving ustekinumab 45 mg (76/79, 96.2%) and 90 mg (74/75, 98.7%). Overall rates of adverse events leading to the withdrawal of the study agent were low and rates were similar to those reported during the placebo-controlled period, with no additional adverse events leading to discontinuation between weeks 12 and 72. The rates of serious adverse events were generally comparable between ustekinumab-treated patients (45 mg, 6/79, 7.6%; 90 mg, 7/75, 9.3%). Infections were reported in 64.6% and 73.3% of patients in the ustekinumab 45 and 90 mg groups, respectively. Two serious infections were reported between weeks 28 and 72, one case each of cellulitis and pharyngitis in the 45 mg group. No cases of TB, non-tuberculous mycobacteria or salmonella infections were reported through the end of the study period. One case of cervical cancer in situ was reported after the placebo-controlled period in a patient in the ustekinumab 45 mg group. No cases of lymphoma were reported throughout the study. Through week 72, no myocardial infarctions or cardiovascular deaths were reported. However, one cerebral hemorrhage was reported in a 55-year-old woman in the 90 mg group after the fourth dose of ustekinumab. No cases of demyelinating neurological disease were reported in this study. The frequency of injection site reactions was 0.1% (1/1211 injections) in the placebo-treated patients and 0.8% (7/847 injections) in the ustekinumab-treated patients. All injection site reactions were mild and did not require any treatment (data not shown). Antibodies against ustekinumab were not associated with injection site reactions, and no cases of serious hypersensitivity or serum sickness-like reactions were reported.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

This is the first phase 2/3 clinical trial of ustekinumab treatment in Japanese patients with moderate-to-severe plaque-type psoriasis. The results of this study suggest that ustekinumab is generally safe and efficacious in Japanese patients with psoriasis. The safety and efficacy data of ustekinumab in this trial are consistent with those reported in two large, phase 3, placebo-controlled, clinical trials in which the majority of patients were white (PHOENIX 120 and PHOENIX 221). The results from the previous studies as well as the current study demonstrate the effectiveness of ustekinumab across different ethnic populations with psoriasis. These findings may have been anticipated by genome-wide association studies that have demonstrated an association between psoriasis and polymorphisms of the genes that encode the shared p40 subunit of IL-12 and IL-23 (IL-12B), and/or one of the IL-23 receptor subunits33 in white,34 Japanese,35 Chinese36 and Thai37 populations.

Ustekinumab was shown to be highly efficacious with a rapid response rate in Japanese patients. A rapid onset of clinical response was observed (as early as week 4). At week 12, PASI 75 responses were achieved in approximately 60% of ustekinumab-treated patients and more than one-third achieved PASI 90 responses. Patients receiving ustekinumab also reported greater improvements in PGA, DLQI, NAPSI, PDI and joint pain scores than patients receiving placebo.

Efficacy was well maintained in this study, in which patients continuously received the same dose of ustekinumab for 1 full year, without interruption or dose adjustment. Response was maintained over time, with 65–80% of ustekinumab-treated patients achieving a PASI 75 response at week 64. Similarly at week 64, one-half of all patients receiving ustekinumab achieved a PASI 90 response. A slightly higher proportion of patients receiving ustekinumab 90 mg achieved a PASI 75 response and/or PASI 90 response compared with patients receiving 45 mg, suggesting that some patients may require higher doses to achieve a full clinical response.

Despite the high burden of disease at baseline in patients enrolled in the Japanese study, ustekinumab showed consistent efficacy in Japanese patients with psoriasis that were comparable to that reported in the PHOENIX 120 and PHOENIX 221 studies. The maintenance of a high level of response through 64 weeks in this study was also consistent with the finding in the PHOENIX 1 trial in which the vast majority of patients who responded to every 12 week dosing continued to maintain PASI 75 through at least week 76.20 Rates of antibodies against ustekinumab were low (6.4%) and comparable to the rates reported in the phase 3, PHOENIX 1 (5.1%) and PHOENIX 2 (5.4%) trials.

In addition to cutaneous improvements, Japanese patients treated with ustekinumab also reported improvements in joint pain (VAS) and nail psoriasis (NAPSI) through week 64. Improvements in NAPSI increased from week 12 to 64 due to the slow growth of nails. Improvement in health-related quality of life was also observed, as assessed by the DLQI, SF-36 and PDI. These improvements were generally maintained through 64 weeks. These findings were consistent with a recent report of improvement in health-related quality of life in ustekinumab-treated patients from the PHOENIX 1 study.32

The results of this study confirmed a favorable safety profile and were consistent with the PHOENIX 120 and PHOENIX 221 trials. Rates and types of adverse events were generally comparable between ustekinumab-treated and placebo-treated patients during the controlled portion of the study. Rates of serious infections and malignancies were low in all groups during the placebo-controlled period. No serious cardiovascular events were reported in the ustekinumab groups, and one case of congestive heart failure was reported in the placebo group at week 12.

Similarly, through week 72, rates of serious infections and malignancies were low and comparable across the ustekinumab treatment groups. No cases of TB were reported in patients treated with ustekinumab, including patients with latent TB receiving concomitant INH therapy. There was one patient with a cerebral hemorrhage, but no myocardial infarctions or cardiovascular deaths were reported in ustekinumab-treated patients through 72 weeks. Rates of injection site reactions and anti-ustekinumab antibodies were low in ustekinumab-treated patients, and consistent with rates reported in the global PHOENIX 120 and 221 trials.

In this study, for the first time, we report that ustekinumab is efficacious and generally well tolerated in Japanese patients with moderate-to-severe plaque-type psoriasis. These findings are consistent with those previously reported in other phase 3 ustekinumab psoriasis clinical trials enrolling patients of other ethnicities.19–21,38 The data presented in this study adds to the growing published work of the use of biologics in Japanese psoriasis patients and support the use of ustekinumab as a new, highly effective treatment option for Japanese patients with moderate-to-severe plaque-type psoriasis.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

The authors wish to thank Kristin Ruley Sharples, Ph.D. of Janssen Biotech for her writing and editorial support in the preparation of this manuscript, Philippe O. Szapary, M.D., MSCE of Centocor Research & Development, Inc., Michael Plotnick, M.D. of Janssen Biotech, and Katsuya Hisamichi, M.D. and Naoko Tejima of Janssen Pharmaceutical K.K. for their input and critical review of the manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

Appendix I

Japanese Ustekinumab Study Group

Osamu Nemoto (Sapporo Skin Clinic), Monji Koga, Jun Mayama (Chitose Skin and Plastic Surgery Clinic), Hidemi Nakagawa (The Jikei University Hospital), Akimichi Morita (Nagoya City University Hospital), Hajime Iizuka (Asahikawa Medical College Hospital), Tadashi Terui (Nihon University Itabashi Hospital), Akira Ozawa (Tokai University Hospital), Osamu Ishikawa (Gunma University Hospital), Shigeru Kawara (Kinki University Hospital), Mamitaro Ohtsuki (Jichi Medical University Hospital), Hidehisa Saeki (The University of Tokyo Hospital), Masahiro Kira (Osaka University Hospital), Yoshihiko Mitsuhashi (Tokyo Medical University Hospital), Shigaku Ikeda (Juntendo University Hospital), Mari Higashiyama (Nissay Hospital), Eiko Toichi, Asuka Wakuda (National Hospital Organization Kyoto Medical Center), Takafumi Etoh (Tokyo Teishin Hospital), Makoto Kawashima (Tokyo Women’s Medical University Hospital), Kazuhiko Takehara (Kanazawa University Hospital), Satoshi Takeuchi (Kyushu University Hospital), Kenzo Takahashi, Akiko Arakawa (Kyoto University Hospital), Takashi Hashimoto (Kurume University Hospital), Shinichi Sato, Kazuhiro Shimizu (Nagasaki University Hospital of Medicine and Dentistry), Hikaru Eto (St Luke’s International Hospital), Juichiro Nakayama (Fukuoka University Hospital), Toshihide Akasaka (Iwate Medical University Hospital), Masahito Tarutani, Kiyofumi Yamanishi (The Hospital of Hyogo College of Medicine), Akihiko Asahina (National Hospital Organization Sagamihara National Hospital), Keiichi Yamanaka (Mie University Hospital), Yujiro Takae (Keio University Hospital), Hideshi Torii (Social Insurance Central General Hospital), Shigetoshi Sano (Kochi Medical School Hospital), Saburo Kishimoto, Norito Kato (University Hospital, Kyoto Prefectural University of Medicine), Koji Sayama (Ehime University Hospital), Ryuhei Okuyama and Tomoyuki Otani (Tohoku University Hospital).