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Pharmacology: Pharmacodynamics: Tumour necrosis factor (TNF) is a dominant cytokine in the inflammatory process of rheumatoid arthritis (RA). Elevated levels of TNF are also found in the synovium and psoriatic plaques of patients 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. Etanercept 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 2 distinct cell surface receptors: The 55-kilodalton (p55) and 75-kilodalton (p75) 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 eg, etanercept 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 RA and ankylosing spondylitis and skin pathology in plaque psoriasis is mediated by pro-inflammatory molecules that are linked in a network controlled by TNF. The mechanism of action of etanercept is thought to be its competitive inhibition of TNF-binding to cell surface TNFR, preventing TNF-mediated cellular responses by rendering TNF biologically inactive. Etanercept may also modulate biologic responses controlled by additional downstream molecules (eg, cytokines, adhesion molecules or proteinases) that are induced or regulated by TNF.
Clinical Trials: This section presents data from 4 randomized controlled trials in RA, 1 study in polyarticular-course juvenile chronic arthritis, 1 study in psoriatic arthritis, 1 study in ankylosing spondylitis and 3 studies in plaque psoriasis.
Rheumatoid Arthritis: The efficacy of Enbrel was assessed in a randomized, double-blind, placebo-controlled study. The study evaluated 234 adult patients with active RA who had failed therapy with at least 1 but no more than 4 disease-modifying antirheumatic drugs (DMARDs). Doses of Enbrel 10 or 25 mg or placebo were administered SC twice a week for 6 consecutive months.
The results of this controlled trial were expressed in percentage improvement in RA using American College of Rheumatology (ACR) response criteria.
ACR 20 and 50 responses were higher in patients treated with Enbrel at 3 and 6 months than in patients treated with placebo (ACR 20: Enbrel 62% and 59%, placebo 23% and 11% at 3 and 6 months, respectively; ACR 50: Enbrel 41% and 40%, placebo 8% and 5% at 3 and 6 months, respectively; p<0.01 Enbrel versus placebo at all time points for both ACR 20 and 50 responses).
Approximately 15% of subjects who received Enbrel achieved an ACR 70 response at months 3 and 6 compared to fewer than 5% of subjects in the placebo arm. Among patients receiving Enbrel, the clinical responses generally appeared within 1-2 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 RA disease activity not included in the ACR response criteria eg, 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. Reintroduction of treatment with Enbrel after discontinuation 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; longer-term experience is not available.
The efficacy of Enbrel was compared to methotrexate in a randomized, active-controlled study with blinded radiographic evaluations as a primary endpoint in 632 adult patients with active RA (<3 years duration) who had never received treatment with methotrexate. Doses of Enbrel 10 or 25 mg 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 trials, and was maintained for up to 24 months. At baseline, patients had a moderate degree of disability, with mean HAQ scores of 1.4-1.5. Treatment with Enbrel 25 mg resulted in substantial improvement at 12 months, with about 44% of patients achieving a normal HAQ scores (<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 following figure. (See Figure 1.)
Click on icon to see table/diagram/imageIn another active-controlled, double-blind, randomized study, clinical efficacy, safety and radiographic progression in RA patients treated with Enbrel alone (25 mg twice weekly), methotrexate alone (7.5-20 mg weekly, median dose 20 mg), and of the combination of Enbrel and methotrexate initiated concurrently were compared in 682 adult patients with active RA 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.
Patients in the Enbrel in combination with methotrexate therapy group had significantly higher ACR 20, 50 and 70 responses, and improvement for DAS and HAQ scores at both 24 and 52 weeks than patients in either of the single therapy groups (see Table 1).
Click on icon to see table/diagram/imageRadiographic progression at week 52 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).
Click on icon to see table/diagram/imageThe percentage of patients without progression (TSS change ≤0.5) was higher in the Enbrel in combination with methotrexate and Enbrel groups compared with methotrexate at week 24 (74%, 68% and 56%, respectively; p<0.05) and week 52 (80%, 68% and 57%, respectively; p<0.05).
The safety and efficacy of Enbrel 50 mg (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 Enbrel 50 mg once weekly, and 153 patients received Enbrel 25 mg twice weekly. The safety and efficacy profiles of the 2 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 2 regimens. A single 50 mg/mL injection of Enbrel was found to be equivalent to 2 simultaneous injection of 25 mg/mL.
Polyarticular-Course Juvenile Chronic Arthritis/Juvenile Rheumatoid Arthritis (JRA): The safety and efficacy of Enbrel were assessed in a 2-part study in 69 children with polyarticular-course JRA who had a variety of JRA onset types. Patients 4-17 years with moderately to severely active polyarticular-course JRA refractory to or intolerant of methotrexate were enrolled; patients remained on a stable dose of a single nonsteroidal anti-inflammatory drug (NSAID) and/or prednisone (≤0.2 mg/kg/day or 10 mg maximum). In part 1, all patients received Enbrel 0.4 mg/kg (maximum 25 mg/dose) SC twice weekly. In part 2, patients with a clinical response at day 90 were randomized to remain on Enbrel or receive placebo for 4 months and assessed for disease flare. Responses were measured using the JRA Definition of Improvement (DOI), defined as ≥30% improvement in at least 3 of 6 and ≥30% worsening in no more than 1 of 6 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 3 of 6 JRA core set criteria and ≥30% improvement in not more than 1 of the 6 JRA core set criteria and a minimum of 2 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. 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.
Studies have not been done in patients with polyarticular-course juvenile chronic arthritis to assess the effects of continued Enbrel therapy in patients who do not respond within 3 months of initiating Enbrel therapy or to assess the combination of Enbrel with methotrexate.
Adults with Psoriatic Arthritis: The efficacy of Enbrel was assessed in a randomized, double-blind, placebo-controlled study in 205 patients with psoriatic arthritis. Patients were between 18 and 70 years and had active psoriatic arthritis (≥3 swollen joints and ≥3 tender joints) in at least 1 of the following forms: Distal interphalangeal (DIP) involvement; polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis); arthritis mutilans; asymmetric psoriatic arthritis; or 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 methotrexate ≤25 mg/week. Doses of Enbrel 25 mg (based on dose-finding studies in patients with RA) or placebo were administered SC twice a week for 6 months.
The results were expressed as percentages of patients achieving the ACR 20, 50 and 70 responses and percentages with improvement in Psoriatic Arthritis Response Criteria (PsARC). Results are summarized in Table 2. (See Table 2.)
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 1st 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.
Adults with Ankylosing Spondylitis: The efficacy of Enbrel was assessed in 3 randomized, double-blind, placebo-controlled studies in 401 patients with ankylosing spondylitis from which 203 were treated with Enbrel. The largest of these trials (n=277) enrolled patients 18-70 years and had active ankylosing spondylitis defined as visual analog 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 noctural 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 Enbrel 25 mg (based on dose-finding studies in patients with RA) or placebo were administered SC 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% or a 70% improvement, respectively.
Compared to placebo, treatment with Enbrel resulted in significant improvements in the ASAS 20, 50 and 70 as early as 2 weeks after the initiation of therapy. (See Table 3.)
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 1st 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.
Adults with Plaque Psoriasis: Enbrel is recommended for use in patients as defined in Indications. Patients who "failed to respond to" in the target population is defined by insufficient response (Psoriasis Area and Severity Index (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 3 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 3 randomized, double-blind, placebo-controlled studies. The primary efficacy endpoint in all 3 studies was the proportion of patients in each treatment group who achieved the PASI 75 (ie, at least a 75% improvement in the PASI score from baseline) at 12 weeks.
Study 1 was a phase II study in patients with active but clinically stable plaque psoriasis involving ≥10% of the body surface area that were ≥18 years old. One hundred and twelve (112) patients were randomized to receive a dose of Enbrel 25 mg (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 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 1 of the previously mentioned 3 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 randomized.
Study 3 evaluated 583 patients and had the same inclusion criteria as study 2. Patients in this study received a dose of Enbrel 25 or 50 mg, or placebo twice a week for 12 weeks and then all patients received open-label Enbrel 25 mg twice weekly for an additional 24 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 4.)
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 1st 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 psoriasis-related serious adverse events were observed. There was some evidence to support a benefit of retreatment with Enbrel in patients initially responding to treatment.
In study 3, the majority of patients (77%) who were initially randomized 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.
Antibodies to Enbrel: Antibodies to Enbrel, all non-neutralizing, were detected in 4 out of 96 RA patients who received Enbrel at a dose of 25 mg twice a week for up to 3 months in a placebo-controlled trial. In the active-controlled trial, 11 (2.8%) of 400 etanercept-treated patients had at least 1 positive result but none of these patients had a positive neutralizing antibody test. Results from JCA patients were similar to those seen in adult RA patients treated with Enbrel. Of 98 patients with psoriatic arthritis who have been tested, no patient has developed antibodies to Enbrel at 24 weeks. Among 175 ankylosing spondylitis patients treated with Enbrel, 3 patients were reported with antibodies to Enbrel, none were neutralizing. In double-blind studies up to 6 months duration in plaque psoriasis, about 1% of the 1084 patients developed antibodies to Enbrel, none were neutralizing.
Although the experience does not exclude the possibility that a clinically relevant effect might occur, no apparent correlation of antibody development to clinical response or adverse event was seen.
Pharmacokinetics: Etanercept serum values were determined by an ELISA method, which may detect ELISA-reactive degradation products as well as the parent compound.
Etanercept is slowly absorbed from the site of SC injection, reaching maximum concentration approximately 48 hrs after a single dose. The absolute bioavailability is 76%. With twice weekly doses, it is anticipated that steady-state concentrations are approximately twice as high as those observed after single doses. After a single SC dose of Enbrel 25 mg, the average maximum serum concentration observed in healthy volunteers was 1.65±0.66 mcg/mL, and the area under the curve (AUC) was 235±96.6 mcg·hr/mL. Dose proportionality has not been formally evaluated, but there is no apparent saturation of clearance across the dosing range.
A biexponential curve is required to describe the concentration-time curve of etanercept. The central volume of distribution of etanercept is 7.6 L, while the volume of distribution at steady-state is 10.4 L.
Etanercept is cleared slowly from the body. The half-life is long, approximately 80 hrs.
Clearance is approximately 175±116 mL/hr in patients with RA, somewhat lower than the value of 131±81 mL/hr observed in healthy volunteers. Additionally, the pharmacokinetics of Enbrel in RA, ankylosing spondylitis and plaque psoriasis patients are similar.
Mean serum concentration profiles at steady state in treated RA patients were Cmax of 2.4 mg/L versus 2.6 mg/L, Cmin of 1.2 mg/L versus 1.4 mg/L, and partial AUC of 297 mg·hr/L versus 316 mg·hr/L for Enbrel 50 mg once weekly (n=21) versus Enbrel 25 mg twice weekly (n=16), respectively.
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 and hepatic impairment should not require a change in dosage. There is no apparent pharmacokinetic difference between men and women.
Methotrexate has no effect on the pharmacokinetics of etanercept. The effect of Enbrel on the human pharmacokinetics of methotrexate has not been investigated.
Elderly Patients: The impact of advanced age was studied in the population pharmacokinetic analysis of etanercept serum concentrations. Clearance and volume estimates in patients 65-87 years were similar to estimates in patients <65 years.
Patients with Renal 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.
Gender: There is no apparent pharmacokinetic difference between men and women.
Concentration-Effect Relationship: Steady-state serum concentration of 1-2 mg/L of etanercept are associated with optimal effect, and are obtained with doses of 25 mg twice weekly.
Patients with Polyarticular-Course Juvenile Chronic Arthritis/Juvenile Rheumatoid Arthritis (JRA): In a polyarticular-course juvenile chronic arthritis trial with Enbrel, 69 patients (aged 4-17 years) were administered Enbrel 0.4 mg/kg twice weekly for 3 months. Serum concentration profiles were similar to those seen in adult RA patients. The youngest children (aged 4 years) had reduced clearance (increased clearance when normalized by weight) compared with older children (aged 12 years) and adults. Simulation of dosing suggests that while older children (aged 10-17 years) will have serum levels close to those seen in adults, younger children will have appreciably lower levels.
Toxicology: Preclinical Safety Data: In the toxicological studies with Enbrel, no dose-limiting or target organ toxicity was evident. Enbrel was considered to be non-genotoxic from a battery of in vitro and in vivo studies. Carcinogenicity studies, and standard assessments of fertility and postnatal toxicity were not performed with Enbrel due to the development of neutralizing antibodies in rodents.
Enbrel did not induce lethality or notable signs of toxicity in mice or rats following a single SC dose of 2000 mg/kg or a single IV dose of 1000 mg/kg. Enbrel did not elicit dose-limiting or target organ toxicity in cynomolgus monkeys following twice-weekly SC administration for 4 or 26 consecutive weeks at a dose (15 mg/kg) that resulted in AUC-based serum drug concentrations that were >27-fold higher than that obtained in humans at the recommended dose of 25 mg.
