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Pharmacology: Pharmacodynamics: Tumour necrosis factor (TNF) is a dominant cytokine in the inflammatory process of rheumatoid arthritis. Elevated levels of TNF are found in the synovial fluid of patients with rheumatoid arthritis and juvenile idiopathic arthritis. Elevated levels of TNF are also found in the synovium and psoriatic plaques of patient with psoriatic arthritis and in serum and synovial tissue of patients with ankylosing spondylitis. In plaque psoriasis, infiltration by inflammatory cells including T-cells leads to increased TNF levels in psoriatic lesions compared with levels in uninvolved skin. ENBREL is a competitive inhibitor of TNF-binding to its cell surface receptors and thereby inhibits the biological activity of TNF. TNF and lymphotoxin are pro-inflammatory cytokines that bind to two distinct cell surface receptors: the 55-kilodalton (p55) and 75-kilodalton (p75) tumour necrosis factor receptors (TNFRs). Both TNFRs exist naturally in membrane-bound and soluble forms. Soluble TNFRs are thought to regulate TNF biological activity.
TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on cross-linking of cell surface TNFRs. Dimeric soluble receptors such as ENBREL possess a higher affinity for TNF than monomeric receptors and are considerably more potent competitive inhibitors of TNF binding to its cellular receptors. In addition, use of an immunoglobulin Fc region as a fusion element in the construction of a dimeric receptor imparts a longer serum half-life.
Mechanism of Action: Much of the joint pathology in rheumatoid arthritis and ankylosing spondylitis and skin pathology in plaque psoriasis is mediated by pro-inflammatory molecules that are linked in a network controlled by TNF. Etanercept is a dimeric soluble form of the p75 TNF (tumour necrosis factor) receptor that can bind to two TNF molecules. The mechanism of action of ENBREL is thought to be its competitive inhibition of both TNF (TNFα) and lymphotoxin alpha [LTα] (TNFβ) to cell surface TNFR, thus rendering TNF biologically inactive and preventing TNF-mediated cellular responses. TNF and LTα are expressed in patients with juvenile idiopathic arthritis. The biological activity of TNF is dependent upon binding to either cell surface receptor. ENBREL may also modulate biologic responses controlled by additional downstream molecules (e.g., cytokines, adhesion molecules, or proteinases) that are induced or regulated by TNF. ENBREL inhibits the activity of TNF in vitro and has been shown to affect several animal models of inflammation, including collagen-induced arthritis in mice.
Clinical Efficacy and Safety: This section presents data from four trials in adults with rheumatoid arthritis, 3 studies in juvenile idiopathic arthritis, 1 study in adults with psoriatic arthritis, 4 studies in adults with ankylosing spondylitis, 2 studies in adults with non-radiographic axial spondyloarthritis, 3 studies in adults with plaque psoriasis and 2 studies in paediatric patients with plaque psoriasis.
Adult Patients with Rheumatoid Arthritis: Placebo-controlled Studies: The efficacy of ENBREL was assessed in a randomised, double-blind, placebo-controlled study. The study evaluated 234 adult patients with active rheumatoid arthritis who had failed therapy with at least one, but no more than four, DMARDs. Doses of 10 mg or 25 mg ENBREL or placebo were administered subcutaneously twice a week for 6 consecutive months. The results of this controlled trial were expressed in percentage improvement in rheumatoid arthritis using American College of Rheumatology (ACR) response criteria.
The primary endpoint was achievement of an ACR 20 response at month 3. Subjects who failed to respond based on pre-specified criteria for lack of efficacy before month 3 were allowed to drop out early and were considered treatment failures. By definition, an ACR 20 response is achieved if a patient experiences a ≥20% improvement in their tender joint count and swollen joint count plus ≥20% improvement in at least three of the following five criteria: (1) patient pain assessment, (2) patient global assessment, (3) physician global assessment, (4) patient self-assessed disability, and (5) acute-phase reactant (erythrocyte sedimentation rate or C-reactive protein). ACR 50 and 70 responses are defined using the same criteria with a 50% improvement or a 70% improvement, respectively.
ACR 20 and 50 responses were higher in patients treated with ENBREL at 3 and 6 months than in patients treated with placebo, at all time points as seen in the table as follows: (See Table 1.)
Click on icon to see table/diagram/imageApproximately 15% of subjects who received ENBREL achieved an ACR 70 response at month 3 and month 6 compared to fewer than 5% of subjects in the placebo arm. 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; results with 10 mg were intermediate between placebo and 25 mg. ENBREL was significantly better than placebo in all components of the ACR criteria, as well as other measures of rheumatoid arthritis disease activity not included in the ACR response criteria, such as morning stiffness. A Health Assessment Questionnaire (HAQ), which included disability, vitality, mental health, general health status, and arthritis-associated health status subdomains, was administered every 3 months during the trial. All subdomains of the HAQ were improved in patients treated with ENBREL compared to controls at 3 and 6 months.
After discontinuation of ENBREL, symptoms of arthritis generally returned within a month. Re-introduction of treatment with ENBREL after discontinuations of up to 24 months resulted in the same magnitudes of responses 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 10 years in open-label extension treatment trials when patients received ENBREL without interruption.
An additional randomised, controlled, double-blind trial evaluated 180 patients with similar criteria to the first study. Doses of 0.25 mg/m2, 2 mg/m2, and 16 mg/m2 ENBREL were administered subcutaneously twice a week for 3 consecutive months. A dose dependent increase in the proportion of subjects achieving an ACR20 response was seen, with 75% of subjects responding in the highest dose group (16 mg/m2 ENBREL).
A second randomised, double-blind, placebo-controlled study also compared the safety and efficacy ENBREL (25 mg) against placebo (SC, twice a week over 6 months) in 89 RA patients in addition to a stable dose of methotrexate. The ACR response criteria were used to assess efficacy. The primary endpoint was achievement of an ACR 20 response at 6 months. Responses were higher in patients treated with ENBREL at 3 and 6 months. Clinical responses in ENBREL-treated patients generally appeared after 1-2 weeks of therapy. In addition, approximately 15% of ENBREL-treated patients achieved an ACR 70 response at month 3 and month 6, compared to less than 5% of subjects in the placebo arm. ENBREL-treated patients experienced significantly greater improvements in all components of the ACR criteria, compared to patients in the placebo arm.
Active-controlled Studies: A randomised, active-controlled study with blinded radiographic evaluation as a primary endpoint compared the efficacy of ENBREL to oral methotrexate in 632 adult patients with active rheumatoid arthritis (<3 years duration) who had never received treatment with methotrexate. The patients had to have >12 tender joints, >10 swollen joints, and either ESR >28 mm/hr, CRP >2.0 mg/dL, or morning stiffness for >45 minutes. Patients were at high risk of erosive disease defined as being rheumatoid factor positive or having at least three erosions at baseline. Doses of 10 mg or 25 mg ENBREL were administered SC twice a week for up to 24 months. Methotrexate doses were escalated from 7.5 mg/week to a maximum of 20 mg/week over the first 8 weeks of the trial and continued for up to 24 months. Clinical improvement including onset of action within 2 weeks with ENBREL 25 mg was similar to that seen in the previous 2 trials, and was maintained for up to 24 months. At baseline, patients had a moderate degree of disability, with mean HAQ scores of 1.4 to 1.5. Treatment with ENBREL 25 mg resulted in substantial improvement at 12 months; with about 44% of patients achieving a normal HAQ score (less than 0.5). This benefit was maintained in Year 2 of this study.
In this study, 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 score (JSN). Radiographs of hands/wrists and feet were read at baseline and 6, 12, and 24 months. The 10 mg ENBREL dose had consistently less effect on structural damage than the 25 mg dose. ENBREL 25 mg was significantly superior to methotrexate for erosion scores at both 12 and 24 months. The differences in TSS and JSN were not statistically significant between methotrexate and ENBREL 25 mg. The results are shown in the figure as follows. (See Figure 1.)
Click on icon to see table/diagram/imageIn another active-controlled, double-blind, randomised study, clinical efficacy, safety, and radiographic progression in RA patients treated with ENBREL alone (25 mg twice weekly), methotrexate alone (7.5 to 20 mg weekly, median dose 20 mg), and of the combination of ENBREL and methotrexate initiated concurrently were compared in 682 adult patients with active rheumatoid arthritis of 6 months to 20 years duration (median 5 years) who had a less than satisfactory response to at least 1 DMARD other than methotrexate.
Forty-three percent of patients had previously received MTX a mean of 2 years prior to the trial at a mean dose of 12.9 mg/week. Patients were excluded from this study if MTX had been discontinued for lack of efficacy or for safety considerations.
Patients in the ENBREL in combination with methotrexate therapy group had significantly higher ACR 20, ACR 50, ACR 70 responses and improvement for disease activity scores (DAS) and HAQ scores at both 24 and 52 weeks than patients in either of the single therapy groups (results shown in table as follows).
Significant advantages for ENBREL in combination with methotrexate compared with ENBREL monotherapy and methotrexate monotherapy were also observed after 24 months. (See Table 2.)
Click on icon to see table/diagram/imageRadiographic progression at 12 months was significantly less in the ENBREL group than in the methotrexate group, while the combination was significantly better than either monotherapy at slowing radiographic progression (see Figure 2 as follows).
Click on icon to see table/diagram/imageSignificant advantages for ENBREL in combination with methotrexate compared with ENBREL monotherapy and methotrexate monotherapy were also observed after 24 months. Similarly, the significant advantages for ENBREL monotherapy compared with methotrexate monotherapy were also observed after 24 months.
In an analysis in which all patients who dropped out of the study for any reason were considered to have progressed, the percentage of patients without progression (TSS change ≤0.5) at 24 months was higher in the ENBREL in combination with methotrexate group compared with the ENBREL alone and methotrexate alone groups (62%, 50%, and 36%, respectively; p<0.05). The difference between ENBREL alone and methotrexate alone was also significant (p<0.05). Among patients who completed a full 24 months of therapy in the study, the non-progression rates were 78%, 70%, and 61%, respectively.
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. In this study, 53 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 regimens were comparable at week 8 in their effect on signs and symptoms of RA; data at week 16 did not show comparability (non-inferiority) between the two regimens.
Paediatric Patients with Juvenile Idiopathic Arthritis: The safety and efficacy of ENBREL were assessed in a two-part study in 69 children with polyarticular-course juvenile chronic arthritis who had a variety of juvenile chronic arthritis onset types (polyarthritis, pauciarthritis, systemic-onset). Patients ages 4 to 17 years with moderately to severely active polyarticular-course juvenile chronic arthritis refractory to or intolerant of methotrexate were enrolled; patients remained on a stable dose of a single non-steroidal 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 subcutaneously twice weekly. In part 2, patients with a clinical response at day 90 were randomised to remain on ENBREL or receive placebo for four months and assessed for disease flare. Responses were measured using the ACR Pedi 30, defined as ≥30% improvement in at least three of six and ≥30% worsening in no more than one of six JRA core set criteria, including active joint count, limitation of motion, physician and patient/parent global assessments, functional assessment, and erythrocyte sedimentation rate (ESR). Disease flare was defined as a ≥30% worsening in three of 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.
In an open-label, safety extension study, 58 paediatric patients from the previously mentioned study (from the age of 4 years at time of enrolment) continued to receive ENBREL for up to 10 years. Rates of serious adverse events and serious infections did not increase with long-term exposure.
In another open-label single-arm study (n=127), 60 patients with extended oligoarthritis (EO) (15 patients aged 2 to 4, 23 patients aged 5 to 11 and 22 patients aged 12 to 17 years old), 38 patients with enthesitis-related arthritis (12 to 17 years old), and 29 patients with psoriatic arthritis (12 to 17 years old) were treated with ENBREL at a dose of 0.8 mg/kg (up to a maximum of 50 mg per dose) administered weekly for 12 weeks. In each of the JIA subtypes, the majority of patients met ACR Pedi 30 criteria and demonstrated clinical improvement in secondary endpoints such as number of tender joints and physician global assessment. The safety profile was consistent with that observed in other JIA studies.
Of the 127 patients in the parent study, 109 participated in the open-label extension study and were followed for an additional 8 years for a total of up to 10 years. At the end of the extension study, 84/109 (77%) patients had completed the study; 27 (25%) while actively taking ENBREL; 7 (6%) had withdrawn from treatment due to low/inactive disease; 5 (5%) had re-started ENBREL following an earlier withdrawal from treatment; and 45 (41%) had stopped ENBREL (but remained under observation); 25/109 (23%) patients permanently discontinued from the study. Improvements in clinical status achieved in the parent study were generally maintained for all efficacy endpoints during the entire follow-up period. Patients actively taking ENBREL could enter an optional withdrawal re-treatment period once during the extension study based on investigator's judgement of clinical response. 30 patients entered the withdrawal period. 17 patients were reported to have a flare (defined as ≥30% worsening in at least 3 of the 6 ACR Pedi components with ≥30% improvement in not more than 1 of the remaining 6 components and a minimum of 2 active joints); median time to flare after ENBREL withdrawal was 190 days. 13 patients were re-treated and the median time to re-treatment from withdrawal was estimated as 274 days. Due to the exploratory nature of these study endpoints and small number of data points, these results should be interpreted with caution.
One malignancy, Hodgkin's disease was reported in the first year of the extension study in an 18 year old EO JIA patient. The number (exposure-adjusted rate per 100 patient years) of serious adverse events, malignancies, and serious infections was 40 (5.85 EP100PY), 1 (0.15 EP100PY), and 14 (2.05 EP100PY), respectively. The safety profile was consistent with that observed in other JIA studies.
Studies have not been done in patients with juvenile idiopathic arthritis to assess the effects of continued ENBREL therapy in patients who do not respond within 3 months of initiating ENBREL therapy. Additionally, studies have not been conducted to assess the effects of reducing the recommended dose of ENBREL following its long-term use in patients with JIA.
Long-term safety of ENBREL monotherapy (n=103), ENBREL plus methotrexate (n=294), or methotrexate monotherapy (n=197) were assessed for up to 3 years in a registry of 594 children aged 2 to 18 years with juvenile idiopathic arthritis, 39 of whom were 2 to 3 years of age. Overall, infections were more commonly reported in patients treated with ENBREL compared to methotrexate alone (3.8% vs. 2%), and the infections associated with ENBREL use were of a more severe nature.
Adult Patients with Psoriatic Arthritis: The efficacy of ENBREL was assessed in a randomised, 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 at least one of the following forms: (1) distal interphalangeal (DIP) involvement; (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis); (3) arthritis mutilans; (4) asymmetric psoriatic arthritis; or (5) spondylitis-like ankylosis. Patients also had plaque psoriasis with a qualifying target lesion ≥2 cm in diameter. Patients had previously been treated with NSAIDs (86%), DMARDs (80%), and corticosteroids (24%). Patients currently on methotrexate therapy (stable for ≥2 months) could continue at a stable dose of ≤25 mg/week of methotrexate. Doses of 25 mg ENBREL (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered SC twice a week for 6 months. At the end of the double-blind study, patients could enter a long-term open-label extension study for a total duration of up to 2 years.
Clinical responses were expressed as percentages of patients achieving the ACR 20, 50, and 70 response and percentages with improvement in Psoriatic Arthritis Response Criteria (PsARC). The PsARC endpoint comprises of four measures: (1) patient global assessment, (2) physician global assessment, (3) joint pain/tenderness score and (4) joint swelling score. Achievement of the PsARC endpoint requires improvement in at least two of the four measures, one of which must be joint pain/tenderness or swelling, and no worsening in any of the four measures. Data have not been evaluated to establish whether ENBREL inhibits progressive joint destruction in psoriatic arthritis. Results are summarised in the table as follows. (See Table 3.)
Click on icon to see table/diagram/imageAmong 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. ENBREL was significantly better than placebo in all measures of disease activity (p <0.001), and responses were similar with and without concomitant methotrexate therapy.
Quality of life in psoriatic arthritis patients was assessed at every timepoint using the disability index of the HAQ. The disability index score was significantly improved at all timepoints in psoriatic arthritis patients treated with ENBREL, relative to placebo (p <0.001). There is insufficient evidence of the efficacy of ENBREL in patients with ankylosing spondylitis-like psoriatic arthropathy due to the small number of patients studied.
Radiographic changes were assessed in the psoriatic arthritis study. Radiographs of hands and wrists were obtained at baseline and months 6, 12, and 24. The modified TSS at 12 months is presented in the table as follows. In an analysis in which all patients who dropped out of the study for any reason were considered to have progressed, the percentage of patients without progression (TSS change ≤0.5) at 12 months was higher in the ENBREL group compared with the placebo group (73% vs. 47%, respectively, p ≤0.001). The effect of ENBREL on radiographic progression was maintained in patients who continued on treatment during the second year. The slowing of peripheral joint damage was observed in patients with polyarticular symmetrical joint involvement. (See Table 4.)
Click on icon to see table/diagram/imageENBREL treatment resulted in improvement in physical function during the double-blind period, and this benefit was maintained during the longer-term exposure of up to 2 years.
There is insufficient evidence of the efficacy of ENBREL in patients with ankylosing spondylitis-like and arthritis mutilans psoriatic arthropathies due to the small number of patients studied.
No study has been performed in patients with psoriatic arthritis using the 50 mg, once weekly dosing regimen. Evidence of efficacy for the once weekly dosing regimen in this patient population has been based on data from the study in patients with ankylosing spondylitis.
Adult Patients with Ankylosing Spondylitis: The efficacy of ENBREL in ankylosing spondylitis was assessed in 3 randomised, double-blind studies comparing twice weekly administration of 25 mg ENBREL with placebo. A total of 401 patients were enrolled, from which 203 were treated with ENBREL. The largest of these trials (n=277) enrolled patients who were between 18 and 70 years of age and had active ankylosing spondylitis defined as a visual analogue scale (VAS) scores of ≥30 for average of duration and intensity of morning stiffness plus VAS scores of ≥30 for at least 2 of the following 3 parameters: patient global assessment; average of VAS values for nocturnal back pain and total back pain; average of 10 questions on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients receiving DMARDs, NSAIDs, or corticosteroids could continue them on stable doses. Patients with complete ankylosis of the spine were not included in the study. Doses of 25 mg of ENBREL (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered subcutaneously twice a week for 6 months in 138 patients.
The primary measure of efficacy (ASAS 20) was a ≥20% improvement in at least 3 of the 4 Assessment in Ankylosing Spondylitis (ASAS) domains (patient global assessments, back pain, BASFI, and inflammation) and absence of deterioration in the remaining domain. ASAS 50 and 70 responses used the same criteria with a 50% improvement or a 70% improvement, respectively.
Compared to placebo, treatment with ENBREL resulted in significant improvements in the ASAS 20, ASAS 50 and ASAS 70 as early as 2 weeks after the initiation of therapy. (See Table 5.)
Click on icon to see table/diagram/imageAmong patients with ankylosing spondylitis who received ENBREL, the clinical responses were apparent at the time of the first visit (2 weeks) and were maintained through 6 months of therapy. Responses were similar in patients who were or were not receiving concomitant therapies at baseline.
Similar results were obtained in the 2 smaller ankylosing spondylitis trials.
In a fourth study, the safety and efficacy of 50 mg ENBREL (two 25 mg SC injections) administered once weekly vs. 25 mg ENBREL administered twice weekly were evaluated in a double-blind, placebo-controlled study of 356 patients with active ankylosing spondylitis. The safety and efficacy profiles of the 50 mg once weekly and 25 mg twice weekly regimens were similar.
Adult Patients with Non-radiographic Axial Spondyloarthritis: Study 1: The efficacy of ENBREL in patients with non-radiographic axial spondyloarthritis (nr-AxSpa) was assessed in a randomised, 12-week double-blind, placebo-controlled study. The study evaluated 215 adult patients (modified intent-to-treat population) with active nr-AxSpa (18 to 49 years of age), defined as those patients meeting the ASAS classification criteria of axial spondyloarthritis but did not meet the modified New York criteria for AS. Patients were also required to have an inadequate response to two or more NSAIDs. In the double-blind period, patients received ENBREL 50 mg weekly or placebo for 12 weeks. The primary measure of efficacy (ASAS 40) was a 40% improvement in at least three of the four ASAS domains and absence of deterioration in the remaining domain. MRIs of the sacroiliac joint and spine were obtained to assess inflammation at baseline and at week 12. The double-blind period was followed by an open-label period during which all patients receive ENBREL 50 mg weekly for up to an additional 92 weeks.
Compared to placebo, treatment with ENBREL resulted in statistically significant improvement in the ASAS 40, ASAS 20 and ASAS 5/6. Significant improvement was also observed for the ASAS partial remission and BASDAI 50. Week 12 results are shown in the table as follows. (See Table 6.)
Click on icon to see table/diagram/imageAt week 12, there was a statistically significant improvement in the SPARCC (Spondyloarthritis Research Consortium of Canada) score for the sacroiliac joint as measured by MRI for patients receiving ENBREL. Adjusted mean change from baseline was 3.8 for ENBREL-treated (n=95) versus 0.8 for placebo-treated (n=105) patients (p <0.001).
Health-related quality of life and physical function were assessed using the BASFI, EuroQol 5D and the SF-36 questionnaires. ENBREL showed statistically significantly greater improvement in the BASFI, EQ5D Overall Health State Score and the SF-36 Physical Component Score (PCS) from baseline to week 12 compared to placebo.
Clinical responses among nr-AxSpa patients who received ENBREL were apparent at the time of the first visit (2 weeks) and were maintained through 2 years of therapy. Improvements in health-related quality of life and physical function were also maintained through 2 years of therapy. The 2 year data did not reveal any new safety findings.
Study 2: This multi-centre, open-label, Phase 4, 3-period study evaluated the withdrawal and re-treatment of ENBREL in patients with active nr-AxSpa who achieved an adequate response (inactive disease defined as Ankylosing Spondylitis Disease Activity Score (ASDAS) C-reactive protein (CRP) less than 1.3) following 24 weeks of treatment.
209 adult patients with active nr-AxSpa (18 to 49 years of age), defined as those patients meeting the Assessment of SpondyloArthritis International Society (ASAS) classification criteria of axial spondyloarthritis (but not meeting the modified New York criteria for AS), having positive MRI findings (active inflammation on MRI highly suggestive of sacroiliitis associated with SpA) and/or positive hsCRP (defined as high sensitivity C-reactive protein [hsCRP] >3 mg/l), and active symptoms defined by an ASDAS CRP greater than or equal to 2.1 at the screening visit received open-label ENBREL 50 mg weekly plus stable background NSAID at the optimal tolerated anti-inflammatory dosage for 24 weeks in Period 1. Patients were also required to have an inadequate response or intolerance to two or more NSAIDs. At week 24, 119 (57%) patients achieved inactive disease and entered into the Period 2 40-week withdrawal phase where subjects discontinued etanercept, yet maintained the background NSAID. The primary measure of efficacy was the occurrence of flare (defined as an ASDAS erythrocyte sedimentation rate (ESR) greater than or equal to 2.1) within 40 weeks following withdrawal of ENBREL. Patients who flared were re-treated with ENBREL 50 mg weekly for 12 weeks (Period 3).
In Period 2, the proportion of patients experiencing ≥1 flare increased from 22% (25/112) at week 4 to 67% (77/115) at week 40. Overall, 75% (86/115) patients experienced a flare at any time point within 40 weeks following withdrawal of ENBREL.
The key secondary objective of Study 2 was to estimate time to flare after withdrawal of ENBREL and additionally compare the time to flare to patients from Study 1 who met the Study 2 withdrawal phase entry requirements and continued ENBREL therapy.
The median time to flare following withdrawal of ENBREL was 16 weeks (95% CI: 13-24 weeks). Less than 25% of patients in Study 1 who did not have treatment withdrawn experienced a flare over the equivalent 40 weeks as in Period 2 Study 2. The time to flare was statistically significantly shorter in subjects who discontinued ENBREL treatment (Study 2) compared to subjects who received continuous etanercept treatment (Study 1), p<0.0001.
Adult Patients with Plaque Psoriasis: ENBREL is recommended for use in patients as defined in Indications/Uses. Patients who 'failed to respond to' in the target population is defined by insufficient response (PASI <50 or PGA less than good), or worsening of the disease while on treatment, and who were adequately dosed for a sufficiently long duration to assess response with at least each of the three major systemic therapies as available.
The efficacy of ENBREL versus other systemic therapies in patients with moderate to severe psoriasis (responsive to other systemic therapies) has not been evaluated in studies directly comparing ENBREL with other systemic therapies. Instead, the safety and efficacy of ENBREL were assessed in four randomised, double-blind, placebo-controlled studies. The primary efficacy endpoint in all three studies was the proportion of patients in each treatment group who achieved the PASI 75 (i.e., at least a 75% improvement in the Psoriasis Area and Severity Index score from baseline) at 12 weeks.
Study 1 was a Phase 2 study in patients with active, but clinically stable plaque psoriasis involving ≥10% of the body surface area who were ≥18 years old. One hundred and twelve (112) patients were randomised to receive a dose of 25 mg of ENBREL (n=57) or placebo (n=55) twice a week for 24 weeks.
Study 2 evaluated 652 patients with chronic plaque psoriasis, using the same inclusion criteria as study 1, with the addition of a minimum psoriasis area and severity index (PASI) of 10 at screening. ENBREL was administered at doses of 25 mg once a week, 25 mg twice a week or 50 mg twice a week for 6 consecutive months. During the first 12 weeks of the double-blind treatment period, patients received placebo or one of the above three ENBREL doses. After 12 weeks of treatment, patients in the placebo group began treatment with blinded ENBREL (25 mg twice a week); patients in the active treatment groups continued to week 24 on the dose to which they were originally randomised.
Study 3 evaluated 583 patients and had the same inclusion criteria as study 2. Patients in this study received a dose of 25 mg or 50 mg ENBREL, or placebo twice a week for 12 weeks, and then all patients received open-label 25 mg ENBREL twice weekly for an additional 24 weeks.
Study 4 evaluated 142 patients and had similar inclusion criteria to studies 2 and 3. Patients in this study received a dose of 50 mg ENBREL or placebo once weekly for 12 weeks and then all patients received open-label 50 mg ENBREL once weekly for an additional 12 weeks.
In study 1, the ENBREL-treated group had a significantly higher proportion of patients with a PASI 75 response at week 12 (30%) compared to the placebo-treated group (2%) (p <0.0001). At 24 weeks, 56% of patients in the ENBREL-treated group had achieved the PASI 75 compared to 5% of placebo-treated patients. Key results of studies 2 and 3 are shown as follows. (See Table 7.)
Click on icon to see table/diagram/imageAmong patients with plaque psoriasis who received ENBREL, significant responses relative to placebo were apparent at the time of the first visit (2 weeks) and were maintained through 24 weeks of therapy.
Study 2 also had a drug withdrawal period, during which patients who achieved a PASI improvement of at least 50% at week 24 had treatment stopped. Patients were observed off treatment for the occurrence of rebound (PASI ≥150% of baseline) and for the time to relapse (defined as a loss of at least half of the improvement achieved between baseline and week 24). During the withdrawal period, symptoms of psoriasis gradually returned with a median time to disease relapse of 3 months. No rebound flare of disease and no psoriasis-related serious adverse events were observed. There was some evidence to support a benefit of re-treatment with ENBREL in patients initially responding to treatment.
In study 3, the majority of patients (77%) who were initially randomised to 50 mg twice weekly and had their ENBREL dose decreased at week 12 to 25 mg twice weekly maintained their PASI 75 response through week 36. For patients who received 25 mg twice weekly throughout the study, the PASI 75 response continued to improve between weeks 12 and 36.
In study 4, the ENBREL-treated group had a higher proportion of patients with PASI 75 at week 12 (38%) compared to the placebo-treated group (2%) (p <0.0001). For patients who received 50 mg once weekly throughout the study, the efficacy responses continued to improve with 71% achieving PASI 75 at week 24.
In long-term (up to 34 months), open-label studies where ENBREL was given without interruption, clinical responses were sustained and safety was comparable to shorter-term studies.
Paediatric Patients with Plaque Psoriasis: The efficacy of ENBREL was assessed in a randomised, double-blind, placebo-controlled study in 211 paediatric patients aged 4 to 17 years with moderate to severe plaque psoriasis (as defined by a sPGA score ≥3, involving ≥10% of the BSA, and PASI ≥12). Eligible patients had a history of receiving phototherapy or systemic therapy, or were inadequately controlled on topical therapy.
Patients received ENBREL 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. At week 12, more patients randomised to ENBREL had positive efficacy responses (e.g., PASI 75) than those randomised to placebo. (See Table 8.)
Click on icon to see table/diagram/imageAfter the 12-week double-blind treatment period, all patients who entered the open-label period received ENBREL 0.8 mg/kg (up to 50 mg) once weekly for additional 24 weeks. Responses observed during the open-label period were similar to those observed in the double-blind period.
During a randomised withdrawal period, significantly more patients re-randomised to placebo experienced disease relapse (loss of PASI 75 response) compared with patients re-randomised to ENBREL. With continued therapy, responses were maintained up to 48 weeks.
The long-term safety and effectiveness of ENBREL 0.8 mg/kg (up to 50 mg) once weekly was assessed in an open-label extension study of 181 paediatric subjects with plaque psoriasis for up to 2 years beyond the 48-week study previously discussed. Long-term experience with ENBREL was generally comparable to the original 48-week study and did not reveal any new safety findings.
Antibodies to ENBREL: Antibodies to etanercept have been detected in the sera of some subjects treated with etanercept. These antibodies have all been non-neutralising and are generally transient. There appears to be no correlation between antibody development and clinical response or adverse events.
In subjects treated with approved doses of etanercept in clinical trials for up to 12 months, cumulative rates of anti-etanercept antibodies were approximately 6% of subjects with rheumatoid arthritis, 7.5% of subjects with psoriatic arthritis, 2% of subjects with ankylosing spondylitis, 7% of subjects with psoriasis, 9.7% of subjects with paediatric psoriasis, and 4.8% of subjects with juvenile idiopathic arthritis.
The proportion of subjects who developed antibodies to etanercept in longer-term trials (of up to 3.5 years) increases over time, as expected. However, due to their transient nature, the incidence of antibodies detected at each assessment point was typically less than 7% in rheumatoid arthritis subjects and psoriasis subjects.
In a long-term psoriasis study in which patients received 50 mg twice weekly for 96 weeks, the incidence of antibodies observed at each assessment point was up to approximately 9%.
Pharmacokinetics: Etanercept serum values were determined by ELISA method, which may detect ELISA-reactive degradation products as well as the parent compound.
Absorption: Etanercept is slowly absorbed from the site of subcutaneous injection, reaching maximum concentration approximately 48 hours after a single dose. The absolute bioavailability is 76% as calculated in a population pharmacokinetic analysis of several studies. With twice weekly doses, it is anticipated that steady-state concentrations may be 2- to 5-fold greater than those observed after single doses.
Serum concentration profiles at steady state were comparable among patients with RA treated with 50 mg ENBREL powder for injection once weekly and those treated with 25 mg ENBREL powder for injection twice weekly. A single 50 mg/mL injection of ENBREL was also found to be bioequivalent to two simultaneous injections of 25 mg/mL. 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). Serum concentrations in patients with rheumatoid arthritis have not been measured for periods of dosing that exceed 6 months. In an open-label, single-dose, two treatment crossover study in healthy volunteers, ENBREL administered as a single injection of ENBREL 50 mg solution for injection was found to be bioequivalent to two simultaneous injections of ENBREL 25 mg powder for injection. The mean (±standard deviation) Cmax and AUC(0-t) are expressed in the table as follows. (See Table 9.)
Click on icon to see table/diagram/imageIn a population pharmacokinetics analysis in ankylosing spondylitis patients the ENBREL steady-state AUCs were 466 mg h/L and 474 mg h/L for 50 mg ENBREL once weekly (n=154) and 25 mg twice weekly (n=148), respectively.
Methotrexate has no effect on the pharmacokinetics of etanercept. The effect of ENBREL on the human pharmacokinetics of methotrexate has not been investigated.
Distribution: After a single subcutaneous dose of 25 mg etanercept, the average maximum serum concentration observed in healthy volunteers was 1.65±0.66 μg/mL, and the area under the curve was 235±96.6 μg·hr/mL. Dose proportionality has not been formally evaluated, but there is no apparent saturation of clearance across the dosing range.
A bi-exponential curve is required to describe the concentration time curve of ENBREL. The central volume of distribution of ENBREL is 7.6 L, while the volume of distribution at steady-state is 13.9±9.4 L.
After continued dosing of RA patients (n=25) with ENBREL for 6 months with 25 mg twice weekly, the median observed level was 3.0 mg/L (range 1.7 to 5.6 mg/L). Based on the available data, individual patients may undergo a 2- to 5-fold increase in serum levels with repeated dosing.
Elimination: Etanercept is cleared slowly from the body. The half-life is long, approximately 80 hours. Clearance is approximately 175±116 mL/hr in patients with rheumatoid arthritis, somewhat lower than the value of 131±81 mL/hr observed in healthy volunteers. Additionally, the pharmacokinetics of etanercept in rheumatoid arthritis patients, plague psoriasis and ankylosing spondylitis patients are similar.
Radioactivity is eliminated in urine after administration of radiolabeled etanercept to patients and volunteers.
Elderly Patients: The impact of advanced age was studied in the population pharmacokinetic analysis of ENBREL serum concentrations. Clearance and volume estimates in patients aged 65 to 87 years were similar to estimates in patients less than 65 years of age.
Renal Impairment or Hepatic Impairment: Although there is elimination of radioactivity in urine after administration of radiolabeled etanercept to patients and volunteers, increased etanercept concentrations were not observed in patients with acute renal or hepatic failure. The presence of renal or hepatic impairment should not require a change in dosage.
Paediatric Patients with Juvenile Idiopathic Arthritis: In a polyarticular-course juvenile chronic arthritis trial with ENBREL, 69 patients (aged 4 to 17 years) were administered 0.4 mg ENBREL/kg twice weekly for three months. Serum concentration profiles were similar to those seen in adult rheumatoid arthritis patients. The youngest children (4 years of age) had reduced clearance (increased clearance when normalised by weight) compared with older children (12 years of age) and adults. Simulation of dosing suggests that while older children (10-17 years of age) will have serum levels close to those seen in adults, younger children will have appreciably lower levels.
Paediatric Patients with Plaque Psoriasis: Patients with paediatric plaque psoriasis (aged 4 to 17 years) were administered 0.8 mg/kg (up to a maximum dose of 50 mg per week) of etanercept once weekly for up to 48 weeks. The mean serum steady-state trough concentrations ranged from 1.6 to 2.1 μg/mL at weeks 12, 24, and 48. These mean concentrations in patients with paediatric plaque psoriasis were similar to the concentrations observed in patients with juvenile idiopathic arthritis (treated with 0.4 mg/kg etanercept twice weekly, up to maximum dose of 50 mg per week). These mean concentrations were similar to those seen in adult patients with plaque psoriasis treated with 25 mg etanercept twice weekly.
Gender: There is no apparent pharmacokinetic difference between men and women.
Paediatric Use: ENBREL has not been studied in children <2 years of age (see Indications/Uses and Dosage & Administration). For paediatric specific safety information concerning malignancies and vaccinations (see Precautions).
Toxicology: Preclinical Safety Data: Carcinogenicity: Long-term animal studies have not been conducted to evaluate the carcinogenic potential of etanercept. Long-term animal studies are not feasible because animals can develop antibodies to etanercept, which is a human protein.
Mutagenicity: Mutagenesis studies were conducted in vitro and in vivo, and no evidence of mutagenic activity was observed.
Impairment of Fertility: Long-term animal studies have not been conducted to evaluate the effect of etanercept on fertility.
