About ENBREL
ENBREL is an anti tumor necrosis factor biologic medication indicated for the treatment of moderate to severe rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, and moderately to severely active polyarticular juvenile idiopathic arthritis. ENBREL has extensive clinical experience:
- In RA, ENBREL has been evaluated in clinical studies over the past 18 years1*
- With the approval for moderate to severe RA in 1998, ENBREL has more than 12 years of postmarketing experience
- 10+ years of continuous safety data in RA clinical studies1
- More than 2.4 million patient-years of experience worldwide across indications1†
*Initial clinical research in RA patients began in 1993.
A History of “1sts” in Each of Its Indications‡
ENBREL has a history of firsts in each of its indications.
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†Based on estimated number of patient-years from 1998 through September 2010. Estimated number of patient-years is calculated based on the number of ENBREL units distributed and an estimated average dose.
‡First tumor necrosis factor (TNF) inhibitor approved in the United States.
§DMARD = disease-modifying antirheumatic drug.
What are some of the attributes of ENBREL?
ENBREL has a mean half-life of ~4.3 days.¶
After administration of 25 mg of ENBREL to 25 patients with rheumatoid arthritis, a mean ± standard deviation half-life of 102 ± 30 hours was observed with clearance of 160 ± 80 mL per hour.3
ENBREL has not been shown to induce neutralizing antibodies.||
Non-neutralizing antibodies were detected in approximately 6% of adult patients with RA, psoriatic arthritis, AS, or plaque psoriasis on ENBREL. There was no apparent correlation of antibody development to clinical response or adverse events.3
||The observed incidence of any antibody positivity is highly dependent on several factors. Therefore, comparison of the incidence of antibodies to ENBREL with the incidence of antibodies to other products may be misleading.
ENBREL is a soluble TNF receptor that binds reversibly with TNF.3,4¶
ENBREL continuously binds and unbinds to TNF.3-5
¶The clinical significance of these attributes is not known.
An Extensive History of Clinical Trial Experience
Proven efficacy in a range of patients, from early to long-standing moderate to severe RA1
Study Descriptions
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The COMET Trial1-3:
Year 1
- 24-month, randomized, double-blind, two-period trial of 542 patients with moderately to severely active RA (from ≥3 months' to ≤2 years' duration). Mean duration of disease for these patients was 9 months
- At baseline: patients were ≥18 years of age, were MTX-naive, had a DAS 28 ≥3.2, had either an erythrocyte sedimentation rate (ESR) ≥28 mm/hr or C-reactive protein (CRP) level ≥20 mg/L, and were within ACR Functional Class I, II, or III
- Corticosteroids (≤10 mg prednisone or equivalent) and NSAIDs were allowed if the dose was stable for at least 4 weeks prior to baseline. The doses were required to be kept constant through 24 weeks unless the patient experienced an adverse event. DMARDs other than MTX and ENBREL were not allowed
Study Design1,2:
- The 2-year COMET trial was divided into two periods, each lasting 1 year
- The primary objective was to compare the effects of ENBREL + MTX to MTX on clinical disease activity and radiographic change over 1 year (Period 1) in subjects with active early RA
- Results for both 1- and 2-year analyses should be viewed in context with the populations evaluated for each time point
- During Period 1 of the trial, patients were randomized to receive once-weekly ENBREL 50 mg in combination with weekly MTX (n = 274) or MTX alone (n = 268). In both the combination and monotherapy groups, initial MTX therapy dose was 7.5 mg, which was titrated to 15 mg at Week 4 if response was inadequate, and further titrated at Week 8 if patients still responded inadequately (maximum dose was 20 mg/week)
- From Weeks 8 to 52, the mean (median) MTX therapy doses were: ENBREL + MTX = 16 mg/week (17 mg/week); MTX monotherapy = 17 mg/week (20 mg/week)
Treatment Groups1,2:
- Subjects were randomized at the baseline visit equally to 1 of 4 groups
- Group 1A: ENBREL + MTX in Periods 1 and 2
- Group 1B: ENBREL + MTX in Period 1 and ENBREL alone in Period 2
- Group 2A: MTX alone in Period 1 and ENBREL + MTX in Period 2
- Group 2B: MTX in Periods 1 and 2
- 131 (24.2%) subjects discontinued during Year 1 of the study: 79 (29.5%) in the MTX group and 52 (19%) in the ENBREL + MTX treatment group
1-Year Endpoints2:
- Clinical endpoints included: DAS 28 clinical remission at Month 12, DAS 44 clinical remission, and ACR 20/50/70
- Radiographic endpoint: change in mTSS at Month 12 (components of TSS are joint space narrowing and joint erosion scores)
Safety Analyses1,2:
- Safety was analyzed using the intent-to-treat (ITT) population (N = 542), which was defined as all enrolled subjects in the trial who received at least 1 dose of the study drug
Efficacy Analyses2:
- The primary clinical efficacy endpoint was DAS 28 clinical remission (<2.6) at Month 12
- For Period 1 analyses, the modified ITT (mITT) population included all subjects who received at least 1 dose of drug and had baseline and ≥1 postbaseline DAS 28 results (N = 265 for ENBREL + MTX, N = 263 for MTX alone)
- The primary radiographic endpoint was the change in mTSS over 12 months
- Radiographic analyses for Period 1 included only subjects with baseline and follow-up x-rays (N = 246 for ENBREL + MTX, N = 230 for MTX alone)
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Year 2
*One subject (Group 1B) discontinued at final Year 1 visit but received 1 dose of the study drug in Year 2 and was included in the Year 2 population.
Study Design1,2:
- The MTX or MTX-matching placebo dose level at the end of Period 1 was the starting dose level for MTX or MTX-matching placebo in Period 2. Subjects in Group 1B (ENBREL + MTX/ENBREL) discontinued MTX by the end of the fourth week of Period 2 (ie, by the start of Month 13 of the study). In Year 2, the mean doses of MTX (mg/week) were similar between groups: 16.19 in Group 1A, 16.26 in Group 1B (mean MTX dose reported was specific to the withdrawal period [~4 weeks]), 17.83 in Group 2A, and 18.03 in Group 2B
Treatment Groups1:
- Subjects who met inclusion criteria for Period 1 and completed Period 1 were eligible to participate in Period 2
- No re-randomization of subjects in Year 2
- 64 patients discontinued during Year 2: 7 in Group 1A, 16 in Group 2A, 18 in Group 1B, and 23 in Group 2B
2-Year Endpoints1:
- Evaluate the safety of each treatment group during Year 2
- Compare the effects of ENBREL + MTX to MTX alone on radiographic change and clinical disease activity in Period 2 in subjects who first received MTX alone for 1 year
- Compare the effects of ENBREL + MTX to ENBREL alone on radiographic change and clinical disease activity in Period 2 in subjects who first received ENBREL + MTX for 1 year
- Compare the effects of ENBREL + MTX for 2 years to MTX alone for 1 year, followed by ENBREL + MTX on radiographic change and clinical disease activity over 2 years
- Compare the effects of ENBREL + MTX on radiographic change and clinical disease activity to MTX alone over 2 years
Safety Analyses1,2:
- The ITT population (N = 411) was defined as all subjects who received at least 1 dose of study drug during Period 2
Efficacy Analyses1:
- The mITT population was defined as all subjects who received at least 1 dose of study drug and had Year 2 baseline and ≥1 post-Year 2 baseline DAS 28 results
- For other analyses, fewer subjects may have been included if they were missing data for that particular endpoint
- Data analyses performed upon completion of Year 2 included data generated by subjects during Year 1 of the COMET trial
- There were 2 baselines for Year 2 analyses: the original baseline at the beginning of Year 1 and the Year 2 baseline (Week 52)
- The radiographic ITT population received at least 1 dose of study drug and provided data at baseline, Year 1, and during Year 2
- Nonresponder imputation (NRI) population analyses included patients who received at least 1 dose of study drug and had at least 1 post-Year 1 baseline on-therapy ACR result (N = 488)
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References
- Data on file, Pfizer Inc.
- Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008;372:375-382.
- Hochberg MC, Chang RW, Dwosh I, Lindsey S, Pincus T, Wolfe F. The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum. 1992;35:498-502.
The Early RA Trial and Open-label Extension Trial1-5:
- Multicenter, double-blind, double-dummy, phase 3 trial
- 632 MTX-naive patients with moderate to severe early RA (≤3 years' duration) were randomized to receive twice-weekly ENBREL 25 mg (n = 207), twice-weekly ENBREL 10 mg (n = 208), or MTX (n = 217). The mean duration of disease for these patients was 11 months
- This trial became open-label and unblinded after all patients had completed 1 year of evaluation. Patients continued through 1 year of follow-up on the treatment to which they had been randomized. At end of year 2, patients switched to or continued twice-weekly ENBREL 25 mg subcutaneously
- Subjects could re-enroll in the continuing open-label portion of the study upon meeting specific predefined re-enrollment inclusion criteria
References
- Enbrel® (etanercept) Prescribing Information. Thousand Oaks, CA: Immunex Corporation; February 2011.
- Data on file, Amgen.
- Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343:1586-1593.
- Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two year radiographic and clinical outcomes. Arthritis Rheum. 2002;46:1443-1450.
- Genovese MC, Bathon JM, Fleischmann RM, et al. Longterm safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumatol. 2005;32:1232-1242.
The Long-Standing RA Open-Label Extension Trial1,2:
- 714 adult patients with moderately to severely active RA (mean duration of disease = 12 years) who had previously inadequate response to one or more DMARDs and had received ENBREL either as monotherapy or in combination with MTX in various clinical trials
- Use of concomitant corticosteroids and/or NSAIDs was permitted during the study
- Most patients received ENBREL 25 mg twice weekly. Because all patients did not enter clinical trials at the same time, length of follow-up varies
- All 714 adult patients who received at least one dose of ENBREL were evaluated for safety. There was no active control or placebo arm in this open-label extension
References
- Moreland LW, Weinblatt ME, Keystone EC, et al. Etanercept treatment in adults with established rheumatoid arthritis: 7 years of clinical experience. J Rheumatol. 2006;33:854-861.
- Data on file, Amgen.
THE TEMPO Trial1-3:
- Multicenter, double-blind, European, Australian, and Israeli trial of 682 patients with moderately to severely active RA (mean duration of disease: 7 years) who had an inadequate response to at least one prior DMARD but were not refractory to MTX
- Patients were randomized to receive MTX monotherapy (n = 228), twice-weekly ENBREL 25 mg as monotherapy (n = 223), or twice-weekly ENBREL 25 mg in combination with MTX (n = 231)
- All patients receiving MTX started at a dose of 7.5 mg/week whereby inadequate responders could be rapidly escalated up to 20 mg/week by Week 8
- Use of concomitant corticosteroids and/or nonsteroidal anti-inflammatory drugs (NSAIDs) was permitted. All data based on ITT, LOCF analysis except where otherwise noted
- The primary clinical endpoint was the area under the curve (AUC) of the ACR numeric score at 24 weeks
- The primary radiographic endpoint was the change from baseline in TSS at 12 months
References
- Enbrel® (etanercept) Prescribing Information. Thousand Oaks, CA: Immunex Corporation; February 2011.
- Klareskog L, van der Heijde D, de Jager JP, et al, for the TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004;363:675-681.
- Data on file, Amgen.