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Enbrel

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Enbrel

CLINICAL PHARMACOLOGY

Mechanism Of Action

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 RA, polyarticular JIA, PsA, and AS and the resulting joint pathology. In addition, TNF plays a role in the inflammatory process of PsO. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, JIA, PsA, AS, and PsO.

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 TNF molecules. Etanercept inhibits binding of TNF-α and TNF-β (lymphotoxin alpha [LT-α]) to cell surface TNFRs, rendering TNF biologically inactive. In in vitro studies, large complexes of etanercept with TNF-α were not detected and cells expressing transmembrane TNF (that binds Enbrel) are not lysed in the presence or absence of complement.

Pharmacodynamics

Etanercept can modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (eg, E-selectin, and to a lesser extent, intercellular adhesion molecule-1 [ICAM-1]), serum levels of cytokines (eg, IL-6), and serum levels of matrix metalloproteinase-3 (MMP-3 or stromelysin). Etanercept has been shown to affect several animal models of inflammation, including murine collagen-induced arthritis.

Pharmacokinetics

After administration of 25 mg of Enbrel by a single 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 2- to 7-fold increase in peak serum concentrations and approximately 4-fold increase in AUC0-72 hr (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 PsO 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 mcg/mL, 1.2 0.7 mcg/mL, and 297 166 mcg•h/mL, respectively, for patients treated with 50 mg Enbrel once weekly (N = 21); and 2.6 1.2 mcg/mL, 1.4 0.7 mcg/mL, and 316 135 mcg•h/mL for patients treated with 25 mg Enbrel twice weekly (N = 16).

Patients with JIA (ages 4 to 17 years) were administered 0.4 mg/kg of Enbrel twice weekly (up to a maximum dose of 50 mg per week) 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 suggest that the clearance of etanercept is reduced slightly in children ages 4 to 8 years. Population pharmacokinetic analyses predict that the pharmacokinetic differences between the regimens of 0.4 mg/kg twice weekly and 0.8 mg/kg once weekly in JIA patients are of the same magnitude as the differences observed between twice weekly and weekly regimens in adult RA patients.

In clinical studies with Enbrel, pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients. The pharmacokinetics of etanercept were unaltered by concomitant MTX in RA patients. No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment on etanercept disposition.

Clinical Studies

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)

Response Placebo Controlled Active Controlled
Study I Study II Study III
Placebo
N = 80
Enbrela
N = 78
MTX/ Placebo
N = 30
MTX/ Enbrela
N = 59
MTX
N = 217
Enbrela
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% 1 5%b 14% 21%c
Month 12 NA NA NA NA 22% 25%
a25 mg Enbrel SC twice weekly
bp < 0.01, Enbrel vs placebo
cp < 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
aValues are medians.
bACR N is the percent improvement based on the same core variables used in defining ACR 20, ACR 50, and ACR 70.
cp < 0.05 for comparisons of Enbrel/MTX vs Enbrel alone or MTX alone.
dMajor 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.

Figure 1: Time Course of ACR 20 Responses

Time Course of ACR 20 Responses - Illustration

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

Parameter (median) Placebo
N = 80
Enbrela
N = 78
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.
a25 mg Enbrel SC twice weekly.
bScale 0-71.
cScale 0-68.
dVisual analog scale: 0 = best; 10 = worst.
eHealth Assessment Questionnaire: 0 = best; 3 = worst; includes eight categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
fp < 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.
ap < 0.05 for comparison of Enbrel vs MTX.
bp < 0.05 for comparison of Enbrel/MTX vs MTX.
cp < 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.

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.

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

Parameter (median) Placebo
N = 104
Enbrela
N = 101
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 assessment 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
ap < 0.001 for all comparisons between Enbrel and placebo at 6 months.
bScale 0-78.
cScale 0-76.
dLikert scale: 0 = best; 5 = worst.
eHealth Assessment Questionnaire: 0 = best; 3 = worst; includes eight categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.
fNormal 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.

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
Enbrel® (etanercept) for Subcutaneous Injection

ASAS 20 Responses in Ankylosing Spondylitis - Illustration

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

Median values at time points Placebo N = 139 Enbrela N = 138
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
ap < 0.0015 for all comparisons between Enbrel and placebo at 6 months. P values for continuous endpoints were based on percent change from baseline.
bMeasured on a Visual Analog Scale (VAS) with 0 = “none” and 100 = “severe.”
cAverage of total nocturnal and back pain scores, measured on a VAS with 0 = “no pain” and 100 = “most severe pain.”
dBath Ankylosing Spondylitis Functional Index (BASFI), average of 10 questions.
eInflammation represented by the average of the last 2 questions on the 6-question Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).
fC-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 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 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 13); patients originally randomized to Enbrel continued on the originally randomized dose (designated as Enbrel/Enbrel groups in Table 13).

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 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 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 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.

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 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 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 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 25 mg BIW
(N = 168)
Enbrel/Enbrel
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%)
ap = 0.001 compared with placebo.
bp < 0.0001 compared with placebo.

Table 14: Study II Outcomes at 3 Months

  Placebo
(N = 204)
Enbrel
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, “cleaf' 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)
ap < 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, 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, among patients 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 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.

REFERENCES

1. National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Incidence Crude Rates, 13 Registries, 1992-2002.

Last reviewed on RxList: 1/14/2014
This monograph has been modified to include the generic and brand name in many instances.

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