14 CLINICAL STUDIES

14.1 Adult Rheumatoid Arthritis

The safety and efficacy of Enbrel were assessed in four randomized, double-blind, controlled studies. The results of all four trials were expressed in percentage of patients with improvement in RA using ACR response criteria.

Study I evaluated 234 patients with active RA who were ≥ 18 years old, had failed therapy with at least one but no more than four disease-modifying antirheumatic drugs (DMARDs) (eg, hydroxychloroquine, oral or injectable gold, MTX, azathioprine, D-penicillamine, sulfasalazine), and had ≥ 12 tender joints, ≥ 10 swollen joints, and either erythrocyte sedimentation rate (ESR) ≥ 28 mm/hr, C-reactive protein (CRP) > 2.0 mg/dL, or morning stiffness for ≥ 45 minutes. Doses of 10 mg or 25 mg Enbrel or placebo were administered SC twice a week for 6 consecutive months.

Study II evaluated 89 patients and had similar inclusion criteria to Study I except that patients in Study II had additionally received MTX for at least 6 months with a stable dose (12.5 to 25 mg/week) for at least 4 weeks and they had at least 6 tender or painful joints. Patients in Study II received a dose of 25 mg Enbrel or placebo SC twice a week for 6 months in addition to their stable MTX dose.

Study III compared the efficacy of Enbrel to MTX in patients with active RA. This study evaluated 632 patients who were ≥ 18 years old with early (≤ 3 years disease duration) active RA, had never received treatment with MTX, and had ≥ 12 tender joints, ≥ 10 swollen joints, and either ESR ≥ 28 mm/hr, CRP > 2.0 mg/dL, or morning stiffness for ≥ 45 minutes. Doses of 10 mg or 25 mg Enbrel were administered SC twice a week for 12 consecutive months. The study was unblinded after all patients had completed at least 12 months (and a median of 17.3 months) of therapy. The majority of patients remained in the study on the treatment to which they were randomized through 2 years, after which they entered an extension study and received open-label 25 mg Enbrel. MTX tablets (escalated from 7.5 mg/week to a maximum of 20 mg/week over the first 8 weeks of the trial) or placebo tablets were given once a week on the same day as the injection of placebo or Enbrel doses, respectively.

Study IV evaluated 682 adult patients with active RA of 6 months to 20 years duration (mean of 7 years) who had an inadequate response to at least one DMARD other than MTX. Forty-three percent of patients had previously received MTX for a mean of 2 years prior to the trial at a mean dose of 12.9 mg. Patients were excluded from this study if MTX had been discontinued for lack of efficacy or for safety considerations. The patient baseline characteristics were similar to those of patients in Study I. Patients were randomized to MTX alone (7.5 to 20 mg weekly, dose escalated as described for Study III; median dose 20 mg), Enbrel alone (25 mg twice weekly), or the combination of Enbrel and MTX initiated concurrently (at the same doses as above). The study evaluated ACR response, Sharp radiographic score, and safety.

Clinical Response

A higher percentage of patients treated with Enbrel and Enbrel in combination with MTX achieved ACR 20, ACR 50, and ACR 70 responses and Major Clinical Responses than in the comparison groups. The results of Studies I, II, and III are summarized in Table 6. The results of Study IV are summarized in Table 7.

Table 6. ACR Responses in Placebo- and Active-Controlled Trials (Percent of Patients)
	Placebo Controlled				Active Controlled
	Study I		Study II		Study III
	Placebo	Enbrela	MTX/Placebo	MTX/Enbrela	MTX	Enbrela
Response	N = 80	N = 78	N = 30	N = 59	N = 217	N = 207
ACR 20
Month 3	23%	62%b	33%	66%b	56%	62%
Month 6	11%	59%b	27%	71%b	58%	65%
Month 12	NA	NA	NA	NA	65%	72%
ACR 50
Month 3	8%	41%b	0%	42%b	24%	29%
Month 6	5%	40%b	3%	39%b	32%	40%
Month 12	NA	NA	NA	NA	43%	49%
ACR 70
Month 3	4%	15%b	0%	15%b	7%	13%c
Month 6	1%	15%b	0%	15%b	14%	21%c
Month 12	NA	NA	NA	NA	22%	25%
a 25 mg Enbrel SC twice weekly. b p < 0.01, Enbrel vs placebo. c p < 0.05, Enbrel vs MTX.

Table 7. Study IV Clinical Efficacy Results: Comparison of MTX vs Enbrel vs Enbrel in Combination with MTX in Patients with Rheumatoid Arthritis of 6 Months to 20 Years Duration (Percent of Patients)
Endpoint	MTX (N = 228)	Enbrel (N = 223)	Enbrel/MTX (N = 231)
ACR Na, b
Month 12	40%	47%	63%c
ACR 20
Month 12	59%	66%	75%c
ACR 50
Month 12	36%	43%	63%c
ACR 70
Month 12	17%	22%	40%c
Major Clinical Responsed	6%	10%	24%c
a Values are medians. b ACR N is the percent improvement based on the same core variables used in defining ACR 20, ACR 50, and ACR 70. c p < 0.05 for comparisons of Enbrel/MTX vs Enbrel alone or MTX alone. d Major clinical response is achieving an ACR 70 response for a continuous 6-month period.

The time course for ACR 20 response rates for patients receiving placebo or 25 mg Enbrel in Studies I and II is summarized in Figure 1. The time course of responses to Enbrel in Study III was similar.

Among patients receiving Enbrel, the clinical responses generally appeared within 1 to 2 weeks after initiation of therapy and nearly always occurred by 3 months. A dose response was seen in Studies I and III: 25 mg Enbrel was more effective than 10 mg (10 mg was not evaluated in Study II). Enbrel was significantly better than placebo in all components of the ACR criteria as well as other measures of RA disease activity not included in the ACR response criteria, such as morning stiffness.

In Study III, ACR response rates and improvement in all the individual ACR response criteria were maintained through 24 months of Enbrel therapy. Over the 2-year study, 23% of Enbrel patients achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6-month period.

The results of the components of the ACR response criteria for Study I are shown in Table 8. Similar results were observed for Enbrel-treated patients in Studies II and III.

Table 8. Components of ACR Response in Study I
	Placebo N = 80			Enbrela N = 78

Parameter (median)	Baseline	3 Months	Baseline		3 Months*
Number of tender joints b	34.0	29.5	31.2		10.0f
Number of swollen joints c	24.0	22.0	23.5		12.6f
Physician global assessment d	7.0	6.5	7.0		3.0f
Patient global assessment d	7.0	7.0	7.0		3.0f
Pain d	6.9	6.6	6.9		2.4f
Disability index e	1.7	1.8	1.6		1.0f
ESR (mm/hr)	31.0	32.0	28.0		15.5f
CRP (mg/dL)	2.8	3.9	3.5		0.9f
* Results at 6 months showed similar improvement. a 25 mg Enbrel SC twice weekly. b Scale 0-71. c Scale 0-68. d Visual analog scale: 0 = best; 10 = worst. e Health Assessment Questionnaire: 0 = best; 3 = worst; includes eight categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. f p < 0.01, Enbrel vs placebo, based on mean percent change from baseline.

After discontinuation of Enbrel, symptoms of arthritis generally returned within a month. Reintroduction of treatment with Enbrel after discontinuations of up to 18 months resulted in the same magnitudes of response as in patients who received Enbrel without interruption of therapy, based on results of open-label studies.

Continued durable responses were seen for over 60 months in open-label extension treatment trials when patients received Enbrel without interruption. A substantial number of patients who initially received concomitant MTX or corticosteroids were able to reduce their doses or discontinue these concomitant therapies while maintaining their clinical responses.

Physical Function Response

In Studies I, II, and III, physical function and disability were assessed using the Health Assessment Questionnaire (HAQ). Additionally, in Study III, patients were administered the SF-36 Health Survey. In Studies I and II, patients treated with 25 mg Enbrel twice weekly showed greater improvement from baseline in the HAQ score beginning in month 1 through month 6 in comparison to placebo (p < 0.001) for the HAQ disability domain (where 0 = none and 3 = severe). In Study I, the mean improvement in the HAQ score from baseline to month 6 was 0.6 (from 1.6 to 1.0) for the 25 mg Enbrel group and 0 (from 1.7 to 1.7) for the placebo group. In Study II, the mean improvement from baseline to month 6 was 0.6 (from 1.5 to 0.9) for the Enbrel/MTX group and 0.2 (from 1.3 to 1.2) for the placebo/MTX group. In Study III, the mean improvement in the HAQ score from baseline to month 6 was 0.7 (from 1.5 to 0.7) for 25 mg Enbrel twice weekly. All subdomains of the HAQ in Studies I and III were improved in patients treated with Enbrel.

In Study III, patients treated with 25 mg Enbrel twice weekly showed greater improvement from baseline in SF-36 physical component summary score compared to Enbrel 10 mg twice weekly and no worsening in the SF-36 mental component summary score. In open-label Enbrel studies, improvements in physical function and disability measures have been maintained for up to 4 years.

In Study IV, median HAQ scores improved from baseline levels of 1.8, 1.8, and 1.8 to 1.1, 1.0, and 0.6 at 12 months in the MTX, Enbrel, and Enbrel/MTX combination treatment groups, respectively (combination versus both MTX and Enbrel, p < 0.01). Twenty-nine percent of patients in the MTX alone treatment group had an improvement of HAQ of at least 1 unit versus 40% and 51% in the Enbrel alone and the Enbrel/MTX combination treatment groups, respectively.

Radiographic Response

In Study III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and joint space narrowing (JSN) score. Radiographs of hands/wrists and forefeet were obtained at baseline, 6 months, 12 months, and 24 months and scored by readers who were unaware of treatment group. The results are shown in Table 9. A significant difference for change in erosion score was observed at 6 months and maintained at 12 months.

Table 9. Mean Radiographic Change Over 6 and 12 Months in Study III
		MTX	25 mg Enbrel	MTX/Enbrel (95% Confidence Interval*)	P Value
12 Months	Total Sharp Score	1.59	1.00	0.59 (-0.12, 1.30)	0.1
	Erosion Score	1.03	0.47	0.56 (0.11, 1.00)	0.002
	JSN Score	0.56	0.52	0.04 (-0.39, 0.46)	0.5

6 Months	Total Sharp Score	1.06	0.57	0.49 (0.06, 0.91)	0.001
	Erosion Score	0.68	0.30	0.38 (0.09, 0.66)	0.001
	JSN Score	0.38	0.27	0.11 (-0.14, 0.35)	0.6
* 95% confidence intervals for the differences in change scores between MTX and Enbrel.

Patients continued on the therapy to which they were randomized for the second year of Study III. Seventy-two percent of patients had x-rays obtained at 24 months. Compared to the patients in the MTX group, greater inhibition of progression in TSS and erosion score was seen in the 25 mg Enbrel group, and, in addition, less progression was noted in the JSN score.

In the open-label extension of Study III, 48% of the original patients treated with 25 mg Enbrel have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage, as measured by the TSS, and 55% of them had no progression of structural damage. Patients originally treated with MTX had further reduction in radiographic progression once they began treatment with Enbrel.

In Study IV, less radiographic progression (TSS) was observed with Enbrel in combination with MTX compared with Enbrel alone or MTX alone at month 12 (Table 10). In the MTX treatment group, 55% of patients experienced no radiographic progression (TSS change ≤ 0.0) at 12 months compared to 63% and 76% in the Enbrel alone and the Enbrel/MTX combination treatment groups, respectively.

Table 10. Mean Radiographic Change in Study IV at 12 Months (95% Confidence Interval)
	MTX (N = 212)*	Enbrel (N = 212)*	Enbrel/MTX (N = 218)*
Total Sharp Score (TSS)	2.80 (1.08, 4.51)	0.52a (-0.10, 1.15)	-0.54b,c (-1.00, -0.07)
Erosion Score (ES)	1.68 (0.61, 2.74)	0.21a (-0.20, 0.61)	-0.30b (-0.65, 0.04)
Joint Space Narrowing (JSN) Score	1.12 (0.34, 1.90)	0.32 (0.00, 0.63)	-0.23b,c (-0.45, -0.02)
* Analyzed radiographic ITT population. a p < 0.05 for comparison of Enbrel vs MTX. b p < 0.05 for comparison of Enbrel/MTX vs MTX. c p < 0.05 for comparison of Enbrel/MTX vs Enbrel.

Once Weekly Dosing

The safety and efficacy of 50 mg Enbrel (two 25 mg SC injections) administered once weekly were evaluated in a double-blind, placebo-controlled study of 420 patients with active RA. Fifty-three patients received placebo, 214 patients received 50 mg Enbrel once weekly, and 153 patients received 25 mg Enbrel twice weekly. The safety and efficacy profiles of the two Enbrel treatment groups were similar.

14.2 Polyarticular Juvenile Idiopathic Arthritis (JIA)

The safety and efficacy of Enbrel were assessed in a 2-part study in 69 children with polyarticular JIA who had a variety of JIA onset types. Patients ages 2 to 17 years with moderately to severely active polyarticular JIA refractory to or intolerant of MTX were enrolled; patients remained on a stable dose of a single nonsteroidal anti-inflammatory drug and/or prednisone (≤ 0.2 mg/kg/day or 10 mg maximum). In part 1, all patients received 0.4 mg/kg (maximum 25 mg per dose) Enbrel SC twice weekly. In part 2, patients with a clinical response at day 90 were randomized to remain on Enbrel or receive placebo for 4 months and assessed for disease flare. Responses were measured using the JIA Definition of Improvement (DOI), defined as ≥ 30% improvement in at least three of six and ≥ 30% worsening in no more than one of the six JIA core set criteria, including active joint count, limitation of motion, physician and patient/parent global assessments, functional assessment, and ESR. Disease flare was defined as a ≥ 30% worsening in three of the six JIA core set criteria and ≥ 30% improvement in not more than one of the six JIA core set criteria and a minimum of two active joints.

In part 1 of the study, 51 of 69 (74%) patients demonstrated a clinical response and entered part 2. In part 2, 6 of 25 (24%) patients remaining on Enbrel experienced a disease flare compared to 20 of 26 (77%) patients receiving placebo (p = 0.007). From the start of part 2, the median time to flare was ≥ 116 days for patients who received Enbrel and 28 days for patients who received placebo. Each component of the JIA core set criteria worsened in the arm that received placebo and remained stable or improved in the arm that continued on Enbrel. The data suggested the possibility of a higher flare rate among those patients with a higher baseline ESR. Of patients who demonstrated a clinical response at 90 days and entered part 2 of the study, some of the patients remaining on Enbrel continued to improve from month 3 through month 7, while those who received placebo did not improve.

The majority of JIA patients who developed a disease flare in part 2 and reintroduced Enbrel treatment up to 4 months after discontinuation re-responded to Enbrel therapy in open-label studies. Most of the responding patients who continued Enbrel therapy without interruption have maintained responses for up to 48 months.

Studies have not been done in patients with polyarticular JIA to assess the effects of continued Enbrel therapy in patients who do not respond within 3 months of initiating Enbrel therapy, or to assess the combination of Enbrel with MTX.

14.3 Psoriatic Arthritis

The safety and efficacy of Enbrel were assessed in a randomized, double-blind, placebo-controlled study in 205 patients with PsA. Patients were between 18 and 70 years of age and had active PsA (≥ 3 swollen joints and ≥ 3 tender joints) in one or more of the following forms: (1) distal interphalangeal (DIP) involvement (N = 104); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis; N = 173); (3) arthritis mutilans (N = 3); (4) asymmetric psoriatic arthritis (N = 81); or (5) ankylosing spondylitis-like (N = 7). Patients also had plaque psoriasis with a qualifying target lesion ≥ 2 cm in diameter. Patients on MTX therapy at enrollment (stable for ≥ 2 months) could continue at a stable dose of ≤ 25 mg/week MTX. Doses of 25 mg Enbrel or placebo were administered SC twice a week during the initial 6-month double-blind period of the study. Patients continued to receive blinded therapy in an up to 6-month maintenance period until all patients had completed the controlled period. Following this, patients received open-label 25 mg Enbrel twice a week in a 12-month extension period.

Compared to placebo, treatment with Enbrel resulted in significant improvements in measures of disease activity (Table 11).

Table 11. Components of Disease Activity in Psoriatic Arthritis
	Placebo N = 104		Enbrela N = 101
Parameter (median)	Baseline	6 Months	Baseline	6 Months
Number of tender jointsb	17.0	13.0	18.0	5.0
Number of swollen jointsc	12.5	9.5	13.0	5.0
Physician global assessmentd	3.0	3.0	3.0	1.0
Patient global assessmentd	3.0	3.0	3.0	1.0
Morning stiffness (minutes)	60	60	60	15
Paind	3.0	3.0	3.0	1.0
Disability indexe	1.0	0.9	1.1	0.3
CRP (mg/dL)f	1.1	1.1	1.6	0.2
a p < 0.001 for all comparisons between Enbrel and placebo at 6 months. b Scale 0-78. c Scale 0-76. d Likert scale: 0 = best; 5 = worst. e Health Assessment Questionnaire: 0 = best; 3 = worst; includes eight categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. f Normal range: 0-0.79 mg/dL.

Among patients with PsA who received Enbrel, the clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. At 6 months, the ACR 20/50/70 responses were achieved by 50%, 37%, and 9%, respectively, of patients receiving Enbrel, compared to 13%, 4%, and 1%, respectively, of patients receiving placebo. Similar responses were seen in patients with each of the subtypes of PsA, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. The results of this study were similar to those seen in an earlier single-center, randomized, placebo-controlled study of 60 patients with PsA.

The skin lesions of psoriasis were also improved with Enbrel, relative to placebo, as measured by percentages of patients achieving improvements in the Psoriasis Area and Severity Index (PASI). Responses increased over time, and at 6 months, the proportions of patients achieving a 50% or 75% improvement in the PASI were 47% and 23%, respectively, in the Enbrel group (N = 66), compared to 18% and 3%, respectively, in the placebo group (N = 62). Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline.

Radiographic Response

Radiographic changes were also assessed in the PsA study. Radiographs of hands and wrists were obtained at baseline and months 6, 12, and 24. A modified Total Sharp Score (TSS), which included distal interphalangeal joints (ie, not identical to the modified TSS used for RA) was used by readers blinded to treatment group to assess the radiographs. Some radiographic features specific to PsA (eg, pencil-and-cup deformity, joint space widening, gross osteolysis, and ankylosis) were included in the scoring system, but others (eg, phalangeal tuft resorption, juxta-articular and shaft periostitis) were not.

Most patients showed little or no change in the modified TSS during this 24-month study (median change of 0 in both patients who initially received Enbrel or placebo). More placebo-treated patients experienced larger magnitudes of radiographic worsening (increased TSS) compared to Enbrel treatment during the controlled period of the study. At 12 months, in an exploratory analysis, 12% (12 of 104) of placebo patients compared to none of the 101 Enbrel-treated patients had increases of 3 points or more in TSS. Inhibition of radiographic progression was maintained in patients who continued on Enbrel during the second year. Of the patients with 1-year and 2-year x-rays, 3% (2 of 71) had increases of 3 points or more in TSS at 1 and 2 years.

Physical Function Response

In the PsA study, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 25 mg Enbrel twice weekly showed greater improvement from baseline in the HAQ-DI score (mean decreases of 54% at both months 3 and 6) in comparison to placebo (mean decreases of 6% at both months 3 and 6) (p < 0.001). At months 3 and 6, patients treated with Enbrel showed greater improvement from baseline in the SF-36 physical component summary score compared to patients treated with placebo, and no worsening in the SF-36 mental component summary score. Improvements in physical function and disability measures were maintained for up to 2 years through the open-label portion of the study.

14.4 Ankylosing Spondylitis

The safety and efficacy of Enbrel were assessed in a randomized, double-blind, placebo-controlled study in 277 patients with active AS. Patients were between 18 and 70 years of age and had AS as defined by the modified New York Criteria for Ankylosing Spondylitis. Patients were to have evidence of active disease based on values of ≥ 30 on a 0-100 unit Visual Analog Scale (VAS) for the average of morning stiffness duration and intensity, and two of the following three other parameters: a) patient global assessment, b) average of nocturnal and total back pain, and c) the average score on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients with complete ankylosis of the spine were excluded from study participation. Patients taking hydroxychloroquine, sulfasalazine, methotrexate, or prednisone (≤ 10 mg/day) could continue these drugs at stable doses for the duration of the study. Doses of 25 mg Enbrel or placebo were administered SC twice a week for 6 months.

The primary measure of efficacy was a 20% improvement in the Assessment in Ankylosing Spondylitis (ASAS) response criteria. Compared to placebo, treatment with Enbrel resulted in improvements in the ASAS and other measures of disease activity (Figure 2 and Table 12).

Figure 2. ASAS 20 Responses in Ankylosing Spondylitis

Figure 2. ASAS 20 Responses in Ankylosing Spondylitis

At 12 weeks, the ASAS 20/50/70 responses were achieved by 60%, 45%, and 29%, respectively, of patients receiving Enbrel, compared to 27%, 13%, and 7%, respectively, of patients receiving placebo (p ≤ 0.0001, Enbrel vs placebo). Similar responses were seen at Week 24. Responses were similar between those patients receiving concomitant therapies at baseline and those who were not. The results of this study were similar to those seen in a single-center, randomized, placebo-controlled study of 40 patients and a multicenter, randomized, placebo-controlled study of 84 patients with AS.

Table 12. Components of Ankylosing Spondylitis Disease Activity
	Placebo N = 139			Enbrela N = 138
Median values at time points	Baseline	6 Months	Baseline		6 Months
ASAS response criteria
Patient global assessment b	63	56	63		36
Back pain c	62	56	60		34
BASFI d	56	55	52		36
Inflammation e	64	57	61		33
Acute phase reactants
CRP (mg/dL) f	2.0	1.9	1.9		0.6
Spinal mobility (cm):
Modified Schober’s test	3.0	2.9	3.1		3.3
Chest expansion	3.2	3.0	3.3		3.9
Occiput-to-wall measurement	5.3	6.0	5.6		4.5
a p < 0.0015 for all comparisons between Enbrel and placebo at 6 months. P values for continuous endpoints were based on percent change from baseline. b Measured on a Visual Analog Scale (VAS) with 0 = “none” and 100 = “severe.” c Average of total nocturnal and back pain scores, measured on a VAS with 0 = “no pain” and 100 = “most severe pain.” d Bath Ankylosing Spondylitis Functional Index (BASFI), average of 10 questions. e Inflammation represented by the average of the last 2 questions on the 6-question Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). f C-reactive protein (CRP) normal range: 0-1.0 mg/dL.

14.5 Adult Plaque Psoriasis

The safety and efficacy of Enbrel were assessed in two randomized, double-blind, placebo-controlled studies in adults with chronic stable PsO involving ≥ 10% of the body surface area, a minimum Psoriasis Area and Severity Index (PASI) score of 10 and who had received or were candidates for systemic antipsoriatic therapy or phototherapy. Patients with guttate, erythrodermic, or pustular psoriasis and patients with severe infections within 4 weeks of screening were excluded from study. No concomitant major antipsoriatic therapies were allowed during the study.

Study I evaluated 672 subjects who received placebo or Enbrel SC at doses of 25 mg once a week, 25 mg twice a week, or 50 mg twice a week for 3 months. After 3 months, subjects continued on blinded treatments for an additional 3 months during which time subjects originally randomized to placebo began treatment with blinded Enbrel at 25 mg twice weekly (designated as placebo/Enbrel in Table 13); subjects originally randomized to Enbrel continued on the originally randomized dose (designated as Enbrel/Enbrel groups in Table 13).

Study II evaluated 611 subjects who received placebo or Enbrel SC at doses of 25 mg or 50 mg twice a week for 3 months. After 3 months of randomized, blinded treatment, subjects in all three arms began receiving open-label Enbrel at 25 mg twice weekly for 9 additional months.

Response to treatment in both studies was assessed after 3 months of therapy and was defined as the proportion of subjects who achieved a reduction in PASI score of at least 75% from baseline. The PASI is a composite score that takes into consideration both the fraction of body surface area affected and the nature and severity of psoriatic changes within the affected regions (induration, erythema and scaling).

Other evaluated outcomes included the proportion of subjects who achieved a score of “clear” or “minimal” by the Static Physician Global Assessment (sPGA) and the proportion of subjects with a reduction of PASI of at least 50% from baseline. The sPGA is a 6-category scale ranging from “5 = severe” to “0 = none” indicating the physician’s overall assessment of the PsO severity focusing on induration, erythema and scaling. Treatment success of “clear” or “minimal” consisted of none or minimal elevation in plaque, up to faint red coloration in erythema and none or minimal fine scale over < 5% of the plaque.

Subjects in all treatment groups and in both studies had a median baseline PASI score ranging from 15 to 17, and the percentage of subjects with baseline sPGA classifications ranged from 54% to 66% for moderate, 17% to 26% for marked and 1% to 5% for severe. Across all treatment groups, the percentage of subjects who previously received systemic therapy for PsO ranged from 61% to 65% in Study I and 71% to 75% in Study II, and those who previously received phototherapy ranged from 44% to 50% in Study I and 72% to 73% in Study II.

More subjects randomized to Enbrel than placebo achieved at least a 75% reduction from baseline PASI score (PASI 75) with a dose response relationship across doses of 25 mg once a week, 25 mg twice a week and 50 mg twice a week (Tables 13 and 14). The individual components of the PASI (induration, erythema and scaling) contributed comparably to the overall treatment-associated improvement in PASI.

Table 13. Study I Outcomes at 3 and 6 Months
		Enbrel/Enbrel
	Placebo/Enbrel 25 mg BIW	25 mg QW	25 mg BIW	50 mg BIW
	(N = 168)	(N = 169)	(N = 167)	(N = 168)
3 Months
PASI 75 n (%)	6 (4%)	23 (14%)a	53 (32%)b	79 (47%)b
Difference (95% CI)		10% (4, 16)	28% (21, 36)	43% (35, 52)
sPGA, “clear” or “minimal” n (%)	8 (5%)	36 (21%)b	53 (32%)b	79 (47%)b
Difference (95% CI)		17% (10, 24)	27% (19, 35)	42% (34, 50)
PASI 50 n (%)	24 (14%)	62 (37%)b	90 (54%)b	119 (71%)b
Difference (95% CI)		22% (13, 31)	40% (30, 49)	57% (48, 65)
6 Months
PASI 75 n (%)	55 (33%)	36 (21%)	68 (41%)	90 (54%)
a p = 0.001 compared with placebo. b p < 0.0001 compared with placebo.

Table 14. Study II Outcomes at 3 Months
		Enbrel
	Placebo	25 mg BIW	50 mg BIW
	(N = 204)	(N = 204)	(N = 203)
PASI 75 n (%)	6 (3%)	66 (32%)a	94 (46%)a
Difference (95% CI)		29% (23, 36)	43% (36, 51)
sPGA, “clear” or “minimal” n (%)	7 (3%)	75 (37%)a	109 (54%)a
Difference (95% CI)		34% (26, 41)	50% (43, 58)
PASI 50 n (%)	18 (9%)	124 (61%)a	147 (72%)a
Difference (95% CI)		52% (44, 60)	64% (56, 71)
a p < 0.0001 compared with placebo.

Among PASI 75 achievers in both studies, the median time to PASI 50 and PASI 75 was approximately 1 month and approximately 2 months, respectively, after the start of therapy with either 25 or 50 mg twice a week.

In Study I, subjects who achieved PASI 75 at month 6 were entered into a study drug withdrawal and retreatment period. Following withdrawal of study drug, these subjects had a median duration of PASI 75 of between 1 and 2 months.

In Study I, among subjects who were PASI 75 responders at 3 months, retreatment with their original blinded Enbrel dose after discontinuation of up to 5 months resulted in a similar proportion of responders as in the initial double-blind portion of the study.

In Study II, most subjects initially randomized to 50 mg twice a week continued in the study after month 3 and had their Enbrel dose decreased to 25 mg twice a week. Of the 91 subjects who were PASI 75 responders at month 3, 70 (77%) maintained their PASI 75 response at month 6.

14.6 Pediatric Plaque Psoriasis

A 48-week, randomized, double-blind, placebo-controlled study enrolled 211 pediatric subjects 4 to 17 years of age, with moderate to severe plaque psoriasis (PsO) (as defined by a sPGA score ≥ 3 [moderate, marked, or severe], involving ≥ 10% of the body surface area, and a PASI score ≥ 12) who were candidates for phototherapy or systemic therapy, or were inadequately controlled on topical therapy. Subjects in all treatment groups had a median baseline PASI score of 16.4, and the percentage of subjects with baseline sPGA classifications was 65% for moderate, 31% for marked, and 3% for severe. Across all treatment groups, the percentage of subjects who previously received systemic or phototherapy for PsO was 57%.

Subjects received Enbrel 0.8 mg/kg (up to a maximum of 50 mg per dose) or placebo once weekly for the first 12 weeks. After 12 weeks, subjects entered a 24-week open-label treatment period, in which all subjects received Enbrel at the same dose. This was followed by a 12-week withdrawal-retreatment period.

Response to treatment was assessed after 12 weeks of therapy and was defined as the proportion of subjects who achieved a reduction in PASI score of at least 75% from baseline. The PASI is a composite score that takes into consideration both the fraction of body surface area affected and the nature and severity of psoriatic changes within the affected regions (induration, erythema and scaling).

Other evaluated outcomes included the proportion of subjects who achieved a score of “clear” or “almost clear” by the sPGA and the proportion of subjects with a reduction in PASI score of at least 90% from baseline. The sPGA is a 6-category scale ranging from “5 = severe” to “0 = none” indicating the physician’s overall assessment of the PsO severity focusing on induration, erythema and scaling. Treatment success of “clear” or “almost clear” consisted of none or minimal elevation in plaque, up to faint red coloration in erythema and none or minimal fine scale over < 5% of the plaque.

Efficacy results are summarized in Table 15.

Table 15. Pediatric Plaque Psoriasis Outcomes at 12 Weeks
	Placebo (N = 105)	Enbrel 0.8 mg/kg Once Weekly (N = 106)
PASI 75, n (%)	12 (11%)	60 (57%)
PASI 90, n (%)	7 (7%)	29 (27%)
sPGA “clear” or “almost clear” n (%)	14 (13%)	55 (52%)

Maintenance of Response

To evaluate maintenance of response, subjects who achieved PASI 75 response at Week 36 were re-randomized to either Enbrel or placebo during a 12-week randomized withdrawal period. The maintenance of PASI 75 response was evaluated at Week 48. The proportion of subjects who maintained PASI 75 response at Week 48 was higher for subjects treated with Enbrel (65%) compared to those treated with placebo (49%).