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Enbrel (Etanercept) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ENBREL® (etanercept) is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of etanercept contains the CH 2 domain, the CH 3 domain and hinge region, but not the CH 1 domain of IgG1. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons.

ENBREL® is supplied as a sterile, white, preservative-free, lyophilized powder for parenteral administration after reconstitution with 1 mL of the supplied Sterile Bacteriostatic Water for Injection (BWFI), USP (containing 0.9% benzyl alcohol). Reconstitution with the supplied BWFI yields a multiple-use, clear, and colorless solution of ENBREL® with a pH of 7.4 ± 0.3. Each vial of ENBREL® contains 25 mg etanercept, 40 mg mannitol, 10 mg sucrose, and 1.2 mg tromethamine.

CLINICAL PHARMACOLOGY

GENERAL

Etanercept binds specifically to tumor necrosis factor (TNF) and blocks its interaction with cell surface TNF receptors. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays an important role in the inflammatory processes of rheumatoid arthritis (RA), polyarticular-course juvenile rheumatoid arthritis (JRA), and ankylosing spondylitis and the resulting joint pathology. In addition, TNF plays a role in the inflammatory process of plaque psoriasis. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, psoriatic arthritis, ankylosing spondylitis (AS), and plaque psoriasis.

Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNFR.

Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind to two TNF molecules. It inhibits the activity of TNF in vitro and has been shown to affect several animal models of inflammation, including murine collagen-induced arthritis. Etanercept inhibits binding of both TNF(alpha) and TNF(beta) (lymphotoxin alpha [LT(alpha)]) to cell surface TNFRs, rendering TNF biologically inactive. Cells expressing transmembrane TNF that bind ENBREL® are not lysed in vitro in the presence or absence of complement.

Etanercept can also modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (i.e., E-selectin and to a lesser extent intercellular adhesion molecule-1 [ICAM-1]), serum levels of cytokines (e.g., IL-6), and serum levels of matrix metalloproteinase-3 (MMP-3 or stromelysin).

PHARMACOKINETICS

After administration of 25 mg of ENBREL® by a single subcutaneous (SC) injection to 25 patients with RA, a mean ± standard deviation half-life of 102 ± 30 hours was observed with a clearance of 160 ± 80 mL/hr. A maximum serum concentration (Cmax) of 1.1 ± 0.6 mcg/mL and time to Cmax of 69 ± 34 hours was observed in these patients following a single 25 mg dose. After 6 months of twice weekly 25 mg doses in these same RA patients, the mean Cmax was 2.4 ± 1.0 mcg/mL (N = 23). Patients exhibited a two- to seven-fold increase in peak serum concentrations and approximately four-fold increase in AUC0-72hr(range 1 to 17 fold) with repeated dosing. Serum concentrations in patients with RA have not been measured for periods of dosing that exceed 6 months. The pharmacokinetic parameters in patients with plaque psoriasis were similar to those seen in patients with RA.

In another study, serum concentration profiles at steady state were comparable among patients with RA treated with 50 mg ENBREL® once weekly and those treated with 25 mg ENBREL® twice weekly. The mean (± standard deviation) Cmax, Cmin, and partial AUC were 2.4 ± 1.5 mg/L, 1.2 ± 0.7 mg/L, and 297 ± 166 mg·h/L, respectively, for patients treated with 50 mg ENBREL® once weekly (N = 21); and 2.6 ± 1.2 mg/L, 1.4 ± 0.7 mg/L, and 316 ± 135 mg·h/L for patients treated with 25 mg ENBREL® twice weekly (N = 16).

Pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients. No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment on ENBREL® disposition.

Patients with JRA (ages 4 to 17 years) were administered 0.4 mg/kg of ENBREL® twice weekly for up to 18 weeks. The mean serum concentration after repeated SC dosing was 2.1 mcg/mL, with a range of 0.7 to 4.3 mcg/mL. Limited data suggests that the clearance of ENBREL® is reduced slightly in children ages 4 to 8 years. Population pharmacokinetic analyses predict that administration of 0.8 mg/kg of ENBREL® once weekly will result in Cmax 11% higher, and Cmin 20% lower at steady state as compared to administration of 0.4 mg/kg of ENBREL® twice weekly. The predicted pharmacokinetic differences between the regimens in JRA patients are of the same magnitude as the differences observed between twice weekly and weekly regimens in adult RA patients. The pharmacokinetics of ENBREL® in children < 4 years of age have not been studied.

CLINICAL STUDIES

ADULT RHEUMATOID ARTHRITIS

The safety and efficacy of ENBREL® were assessed in three randomized, double-blind, controlled studies. 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; e.g., hydroxychloroquine, oral or injectable gold, methotrexate [MTX], azathioprine, D-penicillamine, sulfasalazine), 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® or placebo were administered SC twice a week for 6 consecutive months. Results from patients receiving 25 mg are presented in Table 1.

Study II evaluated 89 patients and had similar inclusion criteria to Study I except that subjects 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. Subjects 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®. Results from patients receiving 25 mg are presented in Table 1. 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.

The results of all three trials were expressed in percentage of patients with improvement in RA using American College of Rheumatology (ACR) response criteria.

CLINICAL RESPONSE

The percent of ENBREL®-treated patients achieving ACR 20, 50, and 70 responses was consistent across all three trials. The results of the three trials are summarized in Table 1.

Table 1:
ACR Responses in Placebo- and Active-Controlled Trials (Percent of Patients)
Placebo Controlled Active Controlled
Study I Study II Study III
Placebo ENBREL® a MTX/
Placebo
MTX/
ENBREL® a
MTX ENBREL® a
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.

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 mea-sures 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 2. Similar results were observed for ENBREL®-treated patients in Studies II and III.

Table 2:
Components of ACR Response in Study I
Placebo
N = 80
ENBREL® a
N = 78
Parameter (median) Baseline 3 Months Baseline 3 Months *
Number of tender joints b 34.0 29.5 31.2 10.0 f
Number of swollen joints c 24.0 22.0 23.5 12.6 f
Physician global assessment d 7.0 6.5 7.0 3.0 f
Patient global assessment d 7.0 7.0 7.0 3.0 f
Pain d 6.9 6.6 6.9 2.4 f
Disability index e 1.7 1.8 1.6 1.0 f
ESR (mm/hr) 31.0 32.0 28.0 15.5 f
CRP (mg/dL) 2.8 3.9 3.5 0.9 f
* 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 Questionnaire1; 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 patients who received ENBREL® without interruption of therapy based on results of open-label studies.

Continued durable responses have been seen for up to 36 months in open-label extension treatment trials when patients received ENBREL® without interruption. Some patients receiving ENBREL® for up to 3 years have been able to dose reduce and even discontinue concomitant steroids and/or methotrexate while maintaining a clinical response.

A Health Assessment Questionnaire (HAQ), 1 which included disability, vitality, mental health, general health status, and arthritis-associated health status subdomains, was administered every 3 months during Studies I and III. All subdomains of the HAQ were improved in patients treated with ENBREL®.

In Study III, health outcome measures were assessed by the SF-36 questionnaire. The eight subscales of the SF-36 were combined into two summary scales, the physical component summary (PCS) and the mental component summary (MCS). 2 At 12 months, patients treated with 25 mg ENBREL® showed significantly more improvement in the PCS compared to the 10 mg ENBREL® group, but not in the MCS. Improvement in the PCS was maintained over the 24 months of ENBREL® therapy.

A 24-week study was conducted in 242 patients with active RA on background methotrexate who were randomized to receive either ENBREL® alone or the combination of ENBREL® and anakinra. The ACR50 response rate was 31% for patients treated with the combination of ENBREL® and anakinra and 41% for patients treated with ENBREL® alone, indicating no added clinical benefit of the combination over ENBREL® alone. Serious infections were increased with the combination compared to ENBREL® alone (see WARNINGS).

PHYSICAL FUNCTION RESPONSE

In Studies I, II, and III, physical function and disability were assessed using the HAQ. 1 Additionally, in Study III, patients were administered the SF-362 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.

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.

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 3. A significant difference for change in erosion score was observed at 6 months and maintained at 12 months.

Table 3:
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) 0.110
   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) 0.529
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) 0.585
* 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, 55% of the original patients treated with 25 mg ENBREL® have been evaluated radiographically at 4 years. Patients had continued inhibition of structural damage, as measured by the TSS, and 65% 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®.

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, 153 patients received 25 mg ENBREL® twice weekly. The safety and efficacy profiles of the two ENBREL® treatment groups were similar.

POLYARTICULAR-COURSE JUVENILE RHEUMATOID ARTHRITIS (JRA)

The safety and efficacy of ENBREL® were assessed in a two-part study in 69 children with polyarticular-course JRA who had a variety of JRA onset types. Patients ages 4 to 17 years with moderately to severely active polyarticular-course JRA refractory to or intolerant of methotrexate 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 four months and assessed for disease flare. Responses were measured using the JRA Definition of Improvement (DOI), 3 defined as >/= 30% improvement in at least three of six and >/= 30% worsening in no more than one of the six JRA 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 JRA core set criteria and >/= 30% improvement in not more than one of the six JRA 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 JRA 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 JRA 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 18 months.

Studies have not been done in patients with polyarticular-course JRA 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 methotrexate.

PSORIATIC ARTHRITIS

The safety and efficacy of ENBREL® were assessed in a randomized, double-blind, placebo-controlled study in 205 patients with psoriatic arthritis. Patients were between 18 and 70 years of age and had active psoriatic arthritis (>/= 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 currently on MTX therapy (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 for 6 months.

Compared to placebo, treatment with ENBREL® resulted in significant improvements in measures of disease activity (Table 4).

Table 4:
Components of Disease Activity in Psoriatic Arthritis
Placebo
N = 104
ENBREL® a
N = 101
Parameter (median) Baseline 6 Months Baseline 6 Months
Number of tender joints b 17.0 13.0 18.0 5.0
Number of swollen joints c 12.5 9.5 13.0 5.0
Physician global assessment d 3.0 3.0 3.0 1.0
Patient global assessment d 3.0 3.0 3.0 1.0
Morning stiffness (minutes) 60 60 60 15
Pain d 3.0 3.0 3.0 1.0
Disability index e 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 Questionnaire1; 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 psoriatic arthritis 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 methotrexate 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 psoriatic arthritis, 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 psoriatic arthritis.

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). 4 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 methotrexate therapy at baseline.

RADIOGRAPHIC RESPONSE

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

Most patients showed little or no change in the modified TSS during this 12-month study (median change of 0 in both treatment and placebo groups). However, there was a difference between groups in the distribution of scores (p = 0.0001, van Elteren test). More placebo-treated patients experienced larger magnitudes of radiographic worsening (increased TSS) compared to ENBREL® treatment. In an exploratory analysis, 12 of 104 placebo patients compared to 0 of 101 ENBREL®-treated patients had increases of points or more in TSS.

ANKYLOSING SPONDYLITIS

The safety and efficacy of ENBREL® were assessed in a randomized, double-blind, placebo-controlled study in 277 patients with active ankylosing spondylitis. Patients were between 18 and 70 years of age and had ankylosing spondylitis as defined by the modified New York Criteria for Ankylosing Spondylitis.5 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 2 of the following 3 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. 6 Compared to placebo, treatment with ENBREL® resulted in improvements in the ASAS and other measures of disease activity (Figure 2 and Table 5).


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 multi-center, randomized, placebo-controlled study of 84 patients with ankylosing spondylitis.

Table 5:
Components of Ankylosing Spondylitis Disease Activity
Placebo
           N = 139            
ENBREL® a
           N = 138           
Mean 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) scale with 0 = "none" and 100 = "severe."
c Average of total nocturnal and back pain scores, measured on a VAS scale 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.

PLAQUE PSORIASIS

The safety and efficacy of ENBREL® were assessed in two randomized, double-blind, placebo-controlled studies in adults with chronic stable plaque psoriasis involving >/= 10% of the body surface area, a minimum PASI of 10 and who had received or were candidates for systemic anti-psoriatic 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 anti-psoriatic therapies were allowed during the study.

Study I evaluated 672 patients 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, patients continued on blinded treatments for an additional 3 months during which time, patients originally randomized to placebo began treatment with blinded ENBREL® at 25 mg twice weekly (designated as placebo/ENBREL® in Table 6); patients originally randomized to ENBREL® continued on the originally randomized dose (designated as ENBREL®/ENBREL® groups in Table 6).

Study II evaluated 611 patients 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, patients 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 patients who achieved a reduction in score of at least 75% from baseline by the Psoriasis Area and Severity Index (PASI). 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 patients who achieved a score of "clear" or "minimal" by the Static Physician Global Assessment (sPGA) and the proportion of patients 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 psoriasis 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.

Patients in all treatment groups and in both studies had a median baseline PASI score ranging from 15 to 17; and the percentage of patients 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 patients who previously received systemic therapy for psoriasis 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 patients 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 6 and 7). The individual components of the PASI (induration, erythema, and scaling) contributed comparably to the overall treatment-associated improvement in PASI.

Table 6: Study I Outcomes at 3 and 6 Months
     ENBREL®/ENBREL®
Placebo/ENBREL®
25 mg BIW
(N = 168)
25 mg QW
  
(N = 169)
25 mg BIW
  
(N = 167)
50 mg BIW
  
(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 7: Study II Outcomes at 3 Months
          ENBREL®
Placebo
(N = 204)
25 mg BIW
(N = 204)
50 mg BIW
(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 and approximately 2 months, respectively, after the start of therapy with either 25 or 50 mg twice a week.

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

In Study I, in patients who were PASI 75 responders at 3 months, retreatment with open-label ENBREL® after discontinuation of up to 5 months resulted in a similar proportion of responders as was seen during the initial double-blind portion of the study.

In Study II, most patients 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 patients who were PASI 75 responders at month 3, 70 (77%) maintained their PASI 75 response at month 6.

Efficacy and safety of ENBREL® treatment beyond 12 months has not been adequately evaluated in patients with psoriasis.

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