INDICATIONS

ENBREL is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis (RA). ENBREL can be initiated in combination with methotrexate (MTX) or used alone.

ENBREL is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis (PsA). ENBREL can be used with or without methotrexate.

ENBREL is indicated for the treatment of patients 4 years or older with chronic moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.

ENBREL is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (AS).

ENBREL is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients ages 2 and older.

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SEAM-RA Study

Evaluation of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects with Rheumatoid Arthritis

SEAM-RA Study

Evaluation of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects with Rheumatoid Arthritis

Study Design

The SEAM-RA Study was a multicenter, randomized, withdrawal, double-blind controlled study that enrolled 371 patients with moderate to severe RA on ENBREL + MTX who had good disease control for 6 months before study entry. The study consisted of a 30-day screening period, a 24-week open-label run-in period, a 48-week double-blind treatment period, and a 30-day safety follow-up period. Eligible patients (n=253) who were in SDAI remission [SDAI ≤ 3.3] were randomized to receive ENBREL + MTX combination therapy (n=51), ENBREL monotherapy (n=101), or MTX monotherapy (n=101).1

Additional Study Details

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Primary endpoint1:

  • Proportion of patients in SDAI remission (SDAI ≤3.3) at Week 48 without disease-worsening on ENBREL monotherapy compared to MTX monotherapy

Select secondary endpoints1:

  • Proportion of patients in SDAI remission at Week 48 without disease-worsening on ENBREL + MTX compared with MTX monotherapy
  • Proportion of patients with disease-worsening and time to disease-worsening in ENBREL monotherapy, MTX monotherapy, and ENBREL + MTX combination therapy
  • Time to recapture SDAI remission after initiating ENBREL + MTX rescue therapy, the proportion of patients with disease-worsening who recaptured SDAI remission with rescue therapy, and their SDAI scores over time
The Enbrel® (etanercept) SEAM-RA double-blind randomized study design had 253 patients with moderate to severe
rheumatoid arthritis (RA) in the double-blind period The Enbrel® (etanercept) SEAM-RA double-blind randomized study design had 253 patients with moderate to severe
rheumatoid arthritis (RA) in the double-blind period

EOS, end of study; MTX, methotrexate; QW, every week.

*DAS 28 allows for up to 6 swollen joints, and a score of <2.6 meets the criteria for remission. SDAI allows for up to 2 swollen joints, and a score of ≤3.3 meets the criteria for remission. DAS 28 requires a value for ESR or CRP and a more complex calculation, for which a calculator may be necessary, while SDAI requires only simple addition of the component values. Lab testing is required.1,3

CRP, C-reactive protein; DAS 28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; SDAI, simple disease activity index.

Baseline Demographics1

Demographic/Characteristics ENBREL
+ MTX
(n=51)
ENBREL
Monotherapy
(n=101)
MTX
Monotherapy
(n=101)
Mean age in years (SD) 55.9
(12.6)
54.8
(12.8)
56.2
(11.4)
% Female 78.4 76.2 75.2
Mean disease duration in years (SD) 10.3
(8.2)
11.0
(7.4)
9.7
(8.0)
% Rheumatoid factor positive 68.6 63.4 58.4
% Anti-CCP positive 68.6 66.3 65.3
Mean MTX dose mg/week (SD) 17.06
(4.99)
15.97
(4.65)
16.26
(4.56)
Mean SDAI score (SD) 1.2
(1.2)
1.3
(1.4)
1.3
(1.0)
Mean HAQ-DI (SE) 0.28
(0.06)
0.26
(0.04)
0.32
(0.04)

Anti-CCP, anti-cyclic citrullinated peptide; HAQ-DI, Health Assessment Questionnaire Disability Index.

Selected Inclusion/Exclusion Criteria4

Inclusion criteria

  • ≥18 years of age at screening
  • A history of RA consistent with the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria
  • In very good RA disease control for ≥6 months in the opinion of the investigator
  • In remission as defined by an SDAI score ≤3.3 at screening (and at end of the run-in period)
  • Received treatment with ENBREL 50 mg per week for RA for ≥6 months prior to run-in visit
  • Received treatment with methotrexate dose of 10 mg to 25 mg weekly for ≥6 months AND on a stable dose of oral methotrexate for ≥8 weeks prior to run-in visit. If subject is taking subcutaneous methotrexate they must switch to an equivalent oral methotrexate dose of 10 mg to 25 mg weekly and remain on a stable oral dose ≥8 weeks prior to run-in visit

Exclusion criteria

  • SDAI >3.3 and ≤11 on two consecutive visits at least 2 weeks apart OR SDAI >3.3 and ≤11 on two or more separate visits OR SDAI >11 at any time during the run-in period
  • Any clinically significant laboratory abnormality during screening or run-in period, which in the opinion of the investigator poses a safety risk, prevented the subject from completing the study, or will interfere with the interpretation of the study results during the run-in period
  • Prior (<6 months) or current use of cyclophosphamide, chlorambucil, nitrogen mustard, or any other alkylating agent
  • Use of any of the following ≤6 months prior to run-in visit: abatacept, anakinra, oral janus kinase inhibitor, azathioprine, cyclosporine, gold, mycophenolate mofetil, Prosorba column, systemic tacrolimus
  • Use of any of the following ≤4 weeks prior to run-in visit: intraarticular, intramuscular, or intravenous corticosteroids, including adrenocorticotropic hormone; intraarticular hyaluronic acid injections; live vaccines
  • Use of leflunomide ≤8 weeks prior to run-in visit

Primary Endpoint

  • Proportion of patients in SDAI remission (SDAI ≤3.3) at Week 48 without disease-worsening on ENBREL monotherapy compared with MTX monotherapy1
    • Patients with disease-worsening had an increased SDAI of >3.3 and ≤11 on two consecutive visits at least 2 weeks apart, or an SDAI of >3.3 and ≤11 at any time on three or more separate visits, or an SDAI of >11 at any time after randomization

Maintenance of SDAI Remission

For patients who achieved remission on ENBREL + MTX, ENBREL monotherapy helped more patients maintain SDAI remission than MTX monotherapy1
Primary endpoint results1
  • The proportion of patients who maintained SDAI remission (SDAI ≤3.3) without disease-worsening at Week 48 was 49.5% of patients on ENBREL monotherapy compared to 28.7% of patients with MTX monotherapy (P=0.004)
    • Patients with disease-worsening had an SDAI of >3.3 and ≤11 on two consecutive visits at least 2 weeks apart, or an SDAI of >3.3 and ≤11 at any time on three or more separate visits, or an SDAI of >11 at any time after randomization
The percent of patients with SDAI remission at Week 48 of the SEAM-RA study was 52.9% for ENBREL plus MTX combination therapy, 49.5% for ENBREL monotherapy, and 28.7% for MTX monotherapy The percent of patients with SDAI remission at Week 48 of the SEAM-RA study was 52.9% for ENBREL plus MTX combination therapy, 49.5% for ENBREL monotherapy, and 28.7% for MTX monotherapy

*Non-responder imputation. The primary analysis set included all randomized subjects. The analysis was conducted according to the original randomization assignment regardless of the actual treatment received during the study (as per intent-to-treat principle).

ENBREL + MTX vs MTX monotherapy. The risk difference and its P value were estimated from the Chi-squared test with continuity correction.

ENBREL monotherapy vs MTX monotherapy. The risk difference and its P value were estimated from the Chi-squared test with continuity correction.

Time to Disease-Worsening

Patients on ENBREL monotherapy maintained SDAI remission without disease-worsening for a longer time compared to MTX monotherapy at Week 481
The Kaplan-Meier curves of time to disease-worsening at 48 weeks in the SEAM-RA study recorded 65.2% for ENBREL plus MTX combination therapy, 59.6% for ENBREL monotherapy, and 38% for MTX monotherapy The Kaplan-Meier curves of time to disease-worsening at 48 weeks in the SEAM-RA study recorded 65.2% for ENBREL plus MTX combination therapy, 59.6% for ENBREL monotherapy, and 38% for MTX monotherapy

Recapturing Remission

Select secondary endpoint results1
  • During the double-blind period, rescue therapy was received by 52% (52/101) of patients in the MTX monotherapy arm, 36% (36/101) in the ENBREL monotherapy arm, and 29% (15/51) in the combination therapy arm
  • The median time to recapture SDAI remission was 12 weeks for patients on ENBREL monotherapy, 11 weeks for patients on MTX monotherapy, and about 11 weeks for patients on ENBREL + MTX
The cumulative proportion of patients who recaptured SDAI remission after initiation of rescue therapy in the SEAM-RA study was 80% for ENBREL plus MTX combination therapy, 75% for ENBREL monotherapy, and 71.2% for MTX monotherapy The cumulative proportion of patients who recaptured SDAI remission after initiation of rescue therapy in the SEAM-RA study was 80% for ENBREL plus MTX combination therapy, 75% for ENBREL monotherapy, and 71.2% for MTX monotherapy

COMET Study

Evaluation of ENBREL + MTX vs MTX in early moderate to severe rheumatoid arthritis (RA)

COMET Study

Evaluation of ENBREL + MTX vs MTX in early moderate to severe rheumatoid arthritis (RA)

Study Design

The COMET study was a 24-month, multicenter, randomized, double-blind, 2-period study of 542 patients with moderately to severely active RA (from ≥3 months‘ to ≤2 years‘ duration) with mean disease duration of 9 months and mean baseline disease activity score (DAS) 28 score of 6.5. 7 In Year 1 of the study, patients were randomized to receive once-weekly ENBREL 50 mg + weekly methotrexate (MTX), up to 20 mg/week (n=274); or MTX alone (n=268). 7 At Year 2, the original combination group either continued combination therapy (n=108) or received ENBREL monotherapy (n=108); the original MTX monotherapy group either received combination therapy (n=88) or continued MTX monotherapy (n=94). 7,8

Additional Study Details

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  • Primary endpoints: DAS 28 remission (DAS 28 <2.6) at Year 1 and change from baseline modified total Sharp score (mTSS) at Year 17
  • Select secondary endpoints: Health assessment questionnaire (HAQ) score at Year 1, HAQ score at Year 2, ACR 20 at Year 1, ACR 70 at Year 17,8

Year 1 COMET Study Arms7

COMET Study Arms for Year 2 Analyses8

Year 1 COMET Study Arms (N=542) and Year 2 COMET Study Arms

Year 1 COMET Study Arms7

Year 1 COMET Study Arms (N=542) and Year 2 COMET Study Arms

COMET Study Arms for Year 2 Analyses8

Year 1 COMET Study Arms (N=542) and Year 2 COMET Study Arms

a One subject (group 1A) discontinued at final Year 1 visit but received one dose of study drug in Year 2 and was included in the Year 2 population.

Select Baseline Demographics7

Mean age 51 years
Percent male/female 26.7%/73.3%
Mean disease duration 9.0 months
Mean HAQ 1.7
Mean DAS 28 6.5
Mean tender joint count 25
Mean swollen joint count 17

Primary Endpoint and ACR Results

Primary endpoint results
  • DAS 28 remission (DAS 28 <2.6) was achieved by 49.8% of patients with ENBREL + MTX vs 27.8% with MTX at Year 1 (P<0.001)9
  • Change from baseline in mTSS at Year 1 was 0.27 for ENBREL + MTX vs 2.44 for MTX (P<0.001)7,10
ACR results
  • ACR 20 was achieved by 86% of patients with ENBREL + MTX vs 67% of patients with MTX at Year 1 (P<0.0001)7
  • ACR 50 was achieved by 71% of patients with ENBREL + MTX vs 49% of patients with MTX at Year 1 (P<0.0001)7
  • ACR 70 was achieved by 48% of patients with ENBREL + MTX vs 28% of patients with MTX at Year 1 (P<0.0001)7

Signs and Symptoms

Significant Symptom and CRP Improvement as Early as Week 2 and Out to Year 1 vs MTX Alone (LOCF)7,9

Significant Symptom and CRP Improvement as Early as Week 2 and Out to Year 1 vs MTX Alone (LOCF) Significant Symptom and CRP Improvement as Early as Week 2 and Out to Year 1 vs MTX Alone (LOCF)
  • Week 2 morning stiffness mean change from baseline: 171 mins for ENBREL + MTX vs 29 mins for MTX alone9
  • Year 1 morning stiffness mean change from baseline: 250 mins for ENBREL + MTX vs 137 mins for MTX alone9
  • Week 2 painful joint count mean improvement from baseline: -10 for ENBREL + MTX vs -3 for MTX alone9
  • Year 1 painful joint count mean improvement from baseline: -20 for ENBREL + MTX vs -15 for MTX alone9

a ENBREL + MTX: n=265, MTX: n=262.

b ENBREL + MTX: n=265, MTX: n=263.

c ENBREL + MTX demonstrated a mean reduction of 27 mm on a visual pain scale of 100 mm at Week 2 compared to 8 mm for MTX alone.

d ENBREL + MTX: n=262, MTX: n=258.

CRP = C-reactive protein; LOCF = last observation carried forward.

Physical Function

ENBREL + MTX can help your patients get back to their everyday activities
Percentage of Patients Who Achieved HAQ ≤0.5 (LOCF)8,9,11,a
Percentage of Patients Who Achieved HAQ Less than or Equal to 0.5 (LOCF) Percentage of Patients Who Achieved HAQ Less than or Equal to 0.5 (LOCF)

a Patients were randomly assigned to 1 of 4 treatment groups (Group 1A, 1B, 2A, or 2B) at the beginning of the study. During Year 1 of the study, Groups 1A and 1B were combined in the ENBREL + MTX treatment arm, and Groups 2A and 2B were combined in the MTX treatment arm. Not all subjects randomized to Year 2 groups were present in the Year 2 efficacy population, due to withdrawals during Year 1. See Study Design for more information about the Year 1 and Year 2 study populations.8

  • Mean HAQ score at baseline was 1.65 in the MTX arm (n=94), 1.62 in the ENBREL + MTX → ENBREL arm (n=108), and 1.76 in the ENBREL + MTX arm (n=108). At Year 2, mean HAQ score was 0.79 in the MTX arm, 0.65 in the ENBREL + MTX → ENBREL arm, and 0.58 in the ENBREL + MTX arm11

* HAQ score of ≤0.5 is consistent with the score of the general population.11

The data points shown at Year 1 represent results for combined study arms (Group 1A + Group 1B and Group 2A + Group 2B) reported at the end of Year 1 of treatment. For the study populations entering Year 2 of treatment, the percentages of patients who had achieved HAQ ≤0.5 at the Year 1 time point were 57%, 62%, 51%, and 43% in Groups 1A, 1B, 2A, and 2B respectively.11

Joint Damage

ENBREL + MTX helps stop further progression of joint damage by Year 18
  • 75% of patients taking ENBREL + MTX had no progression of joint damage at Year 1 (n=246) vs 54% of patients taking MTX alone (n=230)10‡

No progression is defined as a change in mTSS ≤0.0 from baseline.10

Clinical Remission

ENBREL + MTX can help your patients achieve clinical remission

Percentage of Patients Achieving DAS 28 Remission (<2.6) (LOCF)7,9

Percentage of Patients Achieving DAS 28 Remission (Less than 2.6) (LOCF) Percentage of Patients Achieving DAS 28 Remission (Less than 2.6) (LOCF)
  • 50% of patients taking ENBREL + MTX achieved DAS 28 remission vs 28% of patients taking MTX at Year 17
  • Clinical remission does not mean drug-free remission or complete absence of disease12
DAS 28 clinical remission was observed in 7 out of 10 patients when treated earlier (post hoc sub-group analysis of very early RA)12
  • In a post hoc analysis, observed data were analyzed by baseline disease duration (very early RA: ≤4 months, early RA: 4 months to 2 years) and by treatment group (ENBREL + MTX and MTX alone). COMET was not prospectively designed to compare patients with very early RA to those with early RA12
  • 70% of ENBREL + MTX patients (n=63) treated very early vs 35% of MTX patients (n=49) treated very early achieved DAS 28 remission at Year 112
  • Baseline mean DAS 28 scores in patients with very early RA were 6.6 for the ENBREL + MTX arm and 6.7 for the MTX arm12
  • Post hoc analysis is exploratory and no statistical conclusions can be drawn. Interpretation of the results of post hoc analysis is limited

TEMPO Study

Evaluation of ENBREL + MTX vs MTX in moderate to severe RA patients who had failed ≥1 DMARD other than MTX

 

TEMPO Study

Evaluation of ENBREL + MTX vs MTX in moderate to severe RA patients who had failed ≥1 DMARD other than MTX

 

Study Design

The TEMPO Study was a 3-year multicenter, double-blind, randomized, controlled trial (RCT) of 682 patients in Europe, Australia, and Israel with moderate to severe RA (mean disease duration 7 years) who had failed ≥1 disease-modifying antirheumatic drug (DMARD) other than MTX.13-15 Patients received either ENBREL 25 mg biweekly (BIW) + MTX (n=231), ENBREL 25 mg BIW + placebo (n=223), or placebo + MTX (n=228) over 3 years. Use of concomitant corticosteroids and/or NSAIDs was permitted.15-18

Additional Study Details

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  • Primary endpoints: Numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks and change from baseline in mTSS at Year 114
  • Select secondary endpoints: ACR 20, ACR 50, ACR 70, CRP, HAQ score, and DAS 28 clinical remission15

Primary Endpoint and ACR Results

Primary endpoint results:
  • ACR-N AUC was 18.3%-years (95% CI, 17.1-19.6) for ENBREL + MTX, 14.7%-years (95% CI, 13.5-16.0) for ENBREL monotherapy, and 12.2%-years (95% CI, 11.0-13.4) for MTX monotherapy at Week 2419§
  • Mean change in mTSS was -0.5 for ENBREL + MTX, 0.2 for ENBREL monotherapy, and 1.9 for MTX monotherapy at Year 120,21**
ACR results:
  • ACR 20 response (nonresponder imputation [NRI]) at Week 2 was 44% for ENBREL + MTX and 19% for MTX alone22
  • ACR 20/50/70 rates at Week 4 were 58%/20%/7% for ENBREL + MTX and 34%/4%/0% for MTX alone19,22
  • ACR 20/50/70 rates at Year 3 were 52%/43%/31% for ENBREL + MTX and 33%/24%/13% for MTX alone (NRI)22
  • A higher percentage of patients treated with ENBREL and ENBREL + MTX achieved ACR 20, ACR 50, and ACR 70 responses and major clinical responses than in the comparison groups13††

§ ENBREL + MTX vs MTX (P<0.0001); ENBREL vs MTX (P=0.0034); ENBREL + MTX vs ENBREL (P<0.0001).

**ENBREL + MTX vs MTX (P<0.01); ENBREL vs MTX (P<0.01); ENBREL + MTX vs ENBREL (P<0.01).

†† Major clinical response is achieving an ACR 70 response for a continuous 6-month period.

Signs and Symptoms

ENBREL + MTX helps patients feel less joint pain and morning stiffness
Reductions in Pain, Morning Stiffness, and C-Reactive Protein (CRP)23
Reductions in Pain, Morning Stiffness, and C-Reactive Protein (CRP) Reductions in Pain, Morning Stiffness, and C-Reactive Protein (CRP)
  • ENBREL + MTX provided rapid and sustained improvements in clinical signs and symptoms as early as Week 2 and out to Year 322

Physical Function

ENBREL + MTX can help patients get back to their everyday activities

Reductions in HAQ Scores (%)23

Reductions in HAQ Scores (%) Reductions in HAQ Scores (%)

a P<0.01.

ITT = intent-to-treat.

  • ENBREL + MTX provided rapid and sustained improvements in HAQ scores by Week 2 and out to Year 320
  • Mean HAQ score at baseline, Week 2, and Year 3 were 1.7, 1.5, and 1.1 in the MTX arm and 1.8, 1.3, and 0.8 in the ENBREL + MTX arm, respectively20,23
Percentage of Patients Who Achieved HAQ Less Than or Equal to 0.5 (LOCF) Percentage of Patients Who Achieved HAQ Less Than or Equal to 0.5 (LOCF)
  • Half of ENBREL patients achieved a HAQ score consistent with the general population (HAQ ≤0.5)23‡‡
  • Mean HAQ score at baseline was 1.7 in the MTX arm (n=228) and 1.8 in the ENBREL + MTX arm (n=231). At Year 3, mean HAQ score was 1.1 in the MTX arm and 0.8 in the ENBREL + MTX arm16,23

‡‡ HAQ score of ≤0.5 is consistent with the score of the general population.24

Joint Damage

ENBREL + MTX can help stop the progression of joint damage

Mean Change in mTSS20,21

Mean Change in mTSS Mean Change in mTSS

a P<0.01 vs MTX;  b P<0.05 vs MTX; c P<0.01 vs ENBREL.

  • Patients treated with ENBREL + MTX or ENBREL monotherapy experienced significant inhibition of joint damage through Year 320,21,25,26§§
  • ENBREL + MTX and ENBREL monotherapy resulted in significantly less radiographic progression compared with MTX alone20,21
  • Patients with no radiographic progression (Δ mTSS ≤0) at 3 years: 73% in the ENBREL + MTX arm, 60% on ENBREL alone, and 50% on MTX alone21

§§ Per protocol, in order to read the Year 3 data (N=638), the Year 1 (N=648) and Year 2 data (N=622) were reread. Because of known variability in reading of the radiographic images in RA, all radiographs were reread and blinded to patient and time point by the 2 physicians who read the images for the Year 2 report. Thus, the Year 3 scoring of the radiographic images is considered a new reading of the Year 1 and Year 2 time points.

Clinical Remission

ENBREL + MTX helps patients achieve clinical remission

Percentage of Patients Who Achieved DAS 28 Clinical Remission27

Percentage of Patients Who Achieved DAS 28 Clinical Remission Percentage of Patients Who Achieved DAS 28 Clinical Remission
  • Patients treated with ENBREL + MTX experienced rapid and sustained DAS 28 remission by Week 4 and out to Year 327
  • DAS 28 clinical remission does not mean drug-free remission or complete absence of disease27

ERA Study

Evaluation of ENBREL and MTX in early moderate to severe RA, including an analysis of MTX discontinuation

ERA Study

Evaluation of ENBREL and MTX in early moderate to severe RA, including an analysis of MTX discontinuation

 

Study Design

The Early RA (ERA) Study was a 1-year, multicenter, randomized, double-blind study of 632 patients with early moderately to severely active RA (≤3 years‘ duration) with mean disease duration of 11.2 months.13,28,29 In Year 1 of the study, patients were randomized to receive ENBREL 10 mg BIW (n=208), ENBREL 25 mg BIW (n=207), or MTX (up to 20 mg/week, n=217). At Year 2, patients continued in an open-label treatment period. At Year 3, patients switched to or continued ENBREL 25 mg BIW for an open-label extension (n=468). MTX could be continued or started as necessary in the open-label extension (OLE) at the investigator's discretion.30-32

  • All statistical analyses conducted during the OLE are considered descriptive and not confirmatory and therefore are not presented. Consider the following limitations when evaluating OLE results:

    • There is no concurrent control arm, limiting the estimate of treatment effect
    • Data are based only on patients who continued taking ENBREL at each year. Reasons for discontinuation included lack of tolerability, lack of efficacy, and loss to follow-up. Response rates may represent an enriched proportion of patients with continued efficacy and tolerability

Additional Study Details

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  • Primary endpoints: Numeric index of the ACR response (ACR-N) AUC at Month 6 and change from baseline in mTSS at Year 130
  • Baseline patient demographics: Mean age was 50 years, 25% of patients were male, and mean disease duration was 11.2 months.29,32

The ERA Study30,32,34,a

The ERA Study The ERA Study

a At the end of Year 2, patients switched to or continued on ENBREL 25 mg BIW.

Primary Endpoints

  • ACR-N AUC was 15.3 with ENBREL vs 11.5 with MTX at Month 6 (P<0.05)31,33
  • Change from baseline in mTSS was 1.00 with ENBREL vs 1.59 with MTX at Year 1 (P=0.11)31

MTX and Corticosteroid Use

Percent of ENBREL Patients Who Reduced or Discontinued MTX and Corticosteroids29,30

Percent of ENBREL Patients Who Reduced or Discontinued MTX and Corticosteroids Percent of ENBREL Patients Who Reduced or Discontinued MTX and Corticosteroids

a Patients who received MTX during the first 2 years of the study and who started ENBREL in the OLE.

b Change from baseline of OLE.

c Patients who received ENBREL during the first 2 years of the study and continued taking ENBREL in the OLE.

d Change from baseline.

  • Continued durable responses were seen for over 60 months in OLE treatment studies 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 responses13,29

Mean Dose Reductions of MTX and Corticosteroids in ENBREL Patients30

Mean Dose Reductions of MTX and Corticosteroids in ENBREL Patients Mean Dose Reductions of MTX and Corticosteroids in ENBREL Patients

a Patients who received MTX during the first 2 years of the study and who started ENBREL in the OLE.

b Patients who received ENBREL during the first 2 years of the study and continued taking ENBREL in the OLE.

c Change from baseline of OLE.

d Change from baseline.

  • Among 110 patients who received MTX during the first 2 years of the study and who switched to ENBREL during the long-term OLE, 71 were able to discontinue and 20 were able to decrease their dose, 14 maintained their dose, and 5 increased their dose after 3 years in OLE29
  • At 5 years, 44 of 162 patients receiving ENBREL in both the randomized, controlled trial and OLE had also received corticosteroids during the study. Of those 44 patients, 27 were able to discontinue their corticosteroid, 6 were able to decrease their dose, 10 maintained their dose, and 1 increased their dose29,30

Joint Damage

Long-term inhibition of further joint damage through Year 5
  • Change from baseline in mTSS was 1.00 with ENBREL vs 1.59 with MTX at Year 1 (P=0.11)31
  • 48% of the original patients treated with ENBREL were evaluated radiographically at 5 years30
55% had no radiographic progression through 5 years 55% had no radiographic progression through 5 years

No progression is defined as a change in mTSS ≤0.0 from baseline; n=297.

Clinical Remission

A 10-year post hoc analysis of the ERA Study of moderately to severely active early RA
  • >4 out of 10 ENBREL patients had DAS 28 remission at 10 years34

Percentage of Patients Who Achieved DAS 28 Remission (<2.6) (as Observed)34,35,a

Percentage of Patients Who Achieved DAS 28 Remission (Less than 2.6) (as Observed) Percentage of Patients Who Achieved DAS 28 Remission (Less than 2.6) (as Observed)

aIn this study, a modified DAS, DAS 28, was utilized based on a 28-joint count (28 tender and 28 swollen). DAS 28 clinical remission is defined as DAS 28 <2.6 units.

bPatients were administered ENBREL 25 mg BIW monotherapy for the first 2 years, then continued on ENBREL 25 mg BIW with the option to add MTX at any point during the remainder of the study.

cBaseline: n=217; Year 1: n=192; Year 2: n=138.

Limitations of DAS 28 post hoc analysis and OLE
  • DAS 28 was retrospectively calculated based on data collected during the study
  • DAS 28 was not a prespecified endpoint in the controlled portion of the study and was calculated post hoc for each study period from baseline to 10 years
  • Post hoc analysis is exploratory and no statistical conclusions can be drawn
  • There is no concurrent control arm, limiting the estimate of treatment effect
  • Data are based only on patients who continued taking ENBREL at each year. Reasons for discontinuation included lack of tolerability, lack of efficacy, and loss to follow-up. Response rates may represent an enriched proportion of patients with continued efficacy and tolerability

MODERATE TO SEVERE RHEUMATOID ARTHRITIS

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Prescription Enbrel® (etanercept) is administered by injection.

IMPORTANT SAFETY INFORMATION AND INDICATIONS

SERIOUS INFECTIONS

Patients treated with ENBREL are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids or were predisposed to infection because of their underlying disease. ENBREL should not be initiated in the presence of sepsis, active infections, or allergy to ENBREL or its components. ENBREL should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: 1) Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before ENBREL use and periodically during therapy. Treatment for latent infection should be initiated prior to ENBREL use, 2) Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric antifungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness, and 3) Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

The risks and benefits of treatment with ENBREL should be carefully considered prior to initiating therapy in patients 1) with chronic or recurrent infection, 2) who have been exposed to TB, 3) who have resided or traveled in areas of endemic TB or endemic mycoses, or 4) with underlying conditions that may predispose them to infections such as advanced or poorly controlled diabetes. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ENBREL, including the possible development of TB in patients who tested negative for latent TB prior to initiating therapy.

MALIGNANCIES

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including ENBREL.

In adult clinical trials of all TNF blockers, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients. The role of TNF blocker therapy in the development of malignancies is unknown.

Cases of acute and chronic leukemia have been reported in association with postmarketing TNF blocker use in RA and other indications. The risk of leukemia may be higher in patients with RA (approximately 2-fold) than the general population.

Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF blockers, including ENBREL. Periodic skin examinations should be considered for all patients at increased risk for skin cancer.

Pediatric Patients

In patients who initiated therapy at ≤18 years of age, approximately half of the reported malignancies were lymphomas (Hodgkin's and non-Hodgkin's lymphoma). Other cases included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants.

NEUROLOGIC REACTIONS

Treatment with TNF-blocking agents, including ENBREL, has been associated with rare (<0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barré syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with ENBREL therapy. Prescribers should exercise caution in considering the use of ENBREL in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.

CONGESTIVE HEART FAILURE

Cases of worsening congestive heart failure (CHF) and, rarely, new-onset cases have been reported in patients taking ENBREL. Caution should be used when using ENBREL in patients with CHF. These patients should be carefully monitored.

HEMATOLOGIC REACTIONS

Rare cases of pancytopenia, including aplastic anemia, some fatal, have been reported. The causal relationship to ENBREL therapy remains unclear. Exercise caution when considering ENBREL in patients who have a previous history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs or symptoms of blood dyscrasias or infection. Consider discontinuing ENBREL if significant hematologic abnormalities are confirmed.

HEPATITIS B REACTIVATION

Reactivation of hepatitis B has been reported in patients who were previously infected with hepatitis B virus (HBV) and received concomitant TNF-blocking agents, including ENBREL. Most reports occurred in patients also taking immunosuppressive agents, which may contribute to hepatitis B reactivation. Exercise caution when considering ENBREL in these patients.

ALLERGIC REACTIONS

Allergic reactions associated with administration of ENBREL during clinical trials have been reported in <2% of patients. If an anaphylactic reaction or other serious allergic reaction occurs, administration of ENBREL should be discontinued immediately and appropriate therapy initiated.

IMMUNIZATIONS

Live vaccines should not be administered to patients on ENBREL. Pediatric patients, if possible, should be brought up to date with all immunizations prior to initiating ENBREL. In patients with exposure to varicella virus, temporarily discontinue ENBREL and consider prophylactic treatment with Varicella Zoster Immune Globulin.

AUTOIMMUNITY

Autoantibodies may develop with ENBREL, and rarely lupus-like syndrome or autoimmune hepatitis may occur. These may resolve upon withdrawal of ENBREL. Stop ENBREL if lupus-like syndrome or autoimmune hepatitis develops.

WEGENER'S GRANULOMATOSIS PATIENTS

The use of ENBREL in patients with Wegener’s granulomatosis receiving immunosuppressive agents (eg, cyclophosphamide) is not recommended.

MODERATE TO SEVERE ALCOHOLIC HEPATITIS

Based on a study of patients treated for alcoholic hepatitis, exercise caution when using ENBREL in patients with moderate to severe alcoholic hepatitis.

ADVERSE REACTIONS

The most commonly reported adverse reactions in RA clinical trials were injection site reaction and infection. In clinical trials of all other adult indications, adverse reactions were similar to those reported in RA clinical trials.

In general, the adverse reactions in pediatric patients were similar in frequency and type as those seen in adult patients. The types of infections reported in pediatric patients were generally mild and consistent with those commonly seen in the general pediatric population.

DRUG INTERACTIONS

The use of ENBREL in patients receiving concurrent cyclophosphamide therapy is not recommended. The risk of serious infection may increase with concomitant use of abatacept therapy. Concurrent therapy with ENBREL and anakinra is not recommended. Hypoglycemia has been reported following initiation of ENBREL therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.

Please see Prescribing Information and Medication Guide.

INDICATIONS

ENBREL is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis (RA). ENBREL can be initiated in combination with methotrexate (MTX) or used alone.

ENBREL is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis (PsA). ENBREL can be used with or without MTX.

ENBREL is indicated for the treatment of patients 4 years or older with chronic moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.

ENBREL is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (AS).

ENBREL is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients ages 2 and older.

IMPORTANT SAFETY INFORMATION AND INDICATIONS: SERIOUS INFECTIONS

Patients treated with ENBREL are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids or were predisposed to infection because of their underlying disease. ENBREL should not be initiated in the presence of sepsis, active infections, or allergy to ENBREL or its components. ENBREL should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: 1) Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before ENBREL use and periodically during therapy.