ENBREL (Page 8 of 16)

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
(click image for full-size original)

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 versus 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
PlaceboN = 139Enbrel *N = 138
Median values at time pointsBaseline6 MonthsBaseline6 Months
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.
Measured on a Visual Analog Scale (VAS) with 0 = “none” and 100 = “severe”.
Average of total nocturnal and back pain scores, measured on a VAS with 0 = “no pain” and 100 = “most severe pain”.
Bath Ankylosing Spondylitis Functional Index (BASFI), average of 10 questions.
Inflammation represented by the average of the last 2 questions on the 6-question Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).
C-reactive protein (CRP) normal range: 0-1.0 mg/dL.
ASAS response criteria
Patient global assessment 63566336
Back pain 62566034
BASFI §56555236
Inflammation 64576133
Acute phase reactants
CRP (mg/dL) #
Spinal mobility (cm):
Modified Schober’s test3.
Chest expansion3.
Occiput-to-wall measurement5.

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
Placebo/Enbrel Enbrel/Enbrel
25 mg BIW 25 mg QW 25 mg BIW 50 mg BIW
(N = 168) (N = 169) (N = 167) (N = 168)
p = 0.001 compared with placebo.
p < 0.0001 compared with placebo.
3 Months
PASI 75 n (%) 6 (4%) 23 (14%)* 53 (32%) 79 (47%)
Difference (95% CI) 10% (4, 16) 28% (21, 36) 43% (35, 52)
sPGA, “clear” or “minimal” n (%) 8 (5%) 36 (21%) 53 (32%) 79 (47%)
Difference (95% CI) 17% (10, 24) 27% (19, 35) 42% (34, 50)
PASI 50 n (%) 24 (14%) 62 (37%) 90 (54%) 119 (71%)
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%)
Table 14. Study II Outcomes at 3 Months
Placebo Enbrel
25 mg BIW 50 mg BIW
(N = 204) (N = 204) (N = 203)
p < 0.0001 compared with placebo.
PASI 75 n (%) 6 (3%) 66 (32%)* 94 (46%)*
Difference (95% CI) 29% (23, 36) 43% (36, 51)
sPGA, “clear” or “minimal” n (%) 7 (3%) 75 (37%)* 109 (54%)*
Difference (95% CI) 34% (26, 41) 50% (43, 58)
PASI 50 n (%) 18 (9%) 124 (61%)* 147 (72%)*
Difference (95% CI) 52% (44, 60) 64% (56, 71)

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.

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