Etanercept

Etanercept is a fusion protein that blocks tumor necrosis factor alpha (TNF-a) and TNF-b, thereby preventing the excessive stimulation of keratinocytes and other cell types by these cytokines.¹⁸ Etanercept is approved for the treatment of psoriatic arthritis and moderate-to-severe psoriasis. The recommended dose of etanercept in the treatment of psoriasis is 50 mg SC twice weekly (BIW) for 3 months, followed by a reduction to 25 mg SC BIW (or 50 mg once weekly). Other dosing regimens, however, have also been evaluated in clinical studies. The product labeling indicates that there is a risk of serious infection with etanercept and that patients should be evaluated for infection or any predisposition for infection prior to treatment. The labeling also carries a warning about an increased risk of central nervous system (CNS) demyelinating disorders and lymphoma, and there have also been rare cases of lupus-like syndrome in association with etanercept treatment. Patients who develop a new infection or any signs of neurological problems or lymphoma during treatment should be monitored closely and etanercept discontinued if a serious condition is confirmed. Etanercept should also be used with caution in patients with heart failure.¹⁸

Performance in short-term studies

• In a double-blind clinical trial,¹⁹ 34% of patients achieved PASI 75 after 12 weeks and 44% after 24 weeks of therapy with 25 mg etanercept BIW (n=162) (Figure 5). Among patients treated with 50 mg BIW, 49% achieved PASI 75 after 12 weeks and 59% after 24 weeks of therapy. The most common adverse events with etanercept were injection-site reactions, headache, upper respiratory infections, and injection-site ecchymosis. Except for injection-site reactions, the incidence of adverse events with etanercept was similar to that seen in patients given placebo.¹⁹ Similar results were seen in a smaller study that used only the 25 mg twice-weekly dose.²⁰




Figure 5




• In an analysis of the pooled results from one phase 2 and two phase 3 studies of etanercept, 33% of patients achieved PASI 75 at 12 weeks in the 25 mg BIW group (n=415) and 49% in the 50 mg BIW group (n=358). PASI response continued to improve through 16 weeks of therapy and then leveled off.^21,22
• A comprehensive safety analysis that included pooled data from 1261 etanercept- treated psoriasis patients showed rates of adverse effects and infections similar to the placebo group and no reports of opportunistic infections or tuberculosis.²³

Performance in long-term studies

• An integrated analysis of the safety data from one phase 2 and two phase 3 studies included 364 patients treated for at least 12 months and 52 patients treated for at least 15 months. No new or unanticipated pattern of adverse events was observed with extended use of etanercept in this study.²⁴
• An analysis of the long-term safety of etanercept 25 mg BIW in rheumatoid arthritis patients has been conducted.²⁵ This analysis, which included 971 patients who were entering their 6th year of therapy on etanercept 25 mg BIW, demonstrated that rates of serious adverse events and serious infections remained low and stable over time and that there was no evidence of cumulative toxicity using this dose in this type of patient.

Performance in patient subpopulations

• The results from one phase 2 and two phase 3 studies were analyzed according to patient history of psoriasis medication use, specifically methotrexate, cyclosporine, acitretin, psoralen plus ultraviolet A (PUVA), and UVB. Patients with any prior medication use who were treated with 25 mg etanercept BIW (n=351) tended to have had more severe psoriasis at baseline than the study populations in general, but their response to etanercept therapy was similar. There was some evidence, however, that patients with a history of cyclosporine treatment might respond slightly less well to etanercept therapy than those patients without a cyclosporine treatment history.²⁶
• Etanercept is also similarly effective in patients from different demographic subgroups (age, race, or gender).²⁷

Effect on particular features of psoriasis

• In a pooled analysis of two phase 3 clinical trials (328 patients treated with etanercept), etanercept treatment produced rapid and significant improvements in all PASI subscales (erythema, induration, scaling) and all body surface area component scores.²⁸ The proportion of patients achieving 75% improvement in each subscale was 46% for erythema, 51% for induration, and 49% for scaling. In a similar analysis, etanercept was found to also significantly reduce pruritus in psoriasis patients.²⁹

Dosing studies

• Stepped dosing. During the first 12 weeks of a phase 3 study,³⁰ patients were treated with either placebo, etanercept 25 mg BIW, or etanercept 50 mg BIW. For weeks 13 to 24, all patients were treated with etanercept 25 mg BIW. At week 12, more patients achieved PASI 75 in the 50 mg BIW group (49%) than in the 25 mg BIW group (34%). After the switch to 25 mg BIW at week 13, the PASI response was maintained in the 50 mg BIW group (54% of patients at week 24) and continued to gradually increase in the 25 mg BIW group (45% of patients at week 24) (Figure 6).³⁰




Figure 6




• Continued treatment in incomplete responders. A retrospective analysis of two phase 3 studies found that at least 70% of patients treated with 25 mg or 50 mg BIW etanercept had not achieved PASI 50 by week 4. Fifty-one percent of these patients from the 25 mg BIW group and 67% from the 50 mg BIW group subsequently achieved PASI 50 after 12 weeks of etanercept treatment.³¹ In a separate study, patients who had not achieved PASI 50 after 24 weeks of treatment with either 25 mg weekly, 25 mg BIW, or 50 mg BIW etanercept were placed on ongoing open-label treatment with 25 mg BIW etanercept. After a total of 60 weeks of treatment, PASI 75 was achieved by 23% of patients originally on etanercept 25 mg weekly, 27% originally on 25 mg BIW, and 6% originally on 50 mg BIW.³²

Other studies

• Duration of response off treatment and effect of re-treatment after relapse. A total of 409 patients who achieved PASI 50 after 24 weeks of treatment with either 25 mg weekly, 25 mg BIW, or 50 mg BIW etanercept (or 12 weeks of placebo and 12 weeks of 25 mg BIW etanercept) were taken off of all therapy and followed until their psoriasis relapsed (defined as loss of 50% of the PASI improvement achieved during treatment). The median time to relapse ranged from 85 to 112 days depending on dose (Figure 7), and there was only 1 case of rebound (in the 25 mg weekly dose group). Patients who had relapsed could be effectively re-treated with their original dose of etanercept. Re-treatment achieved PASI 75 response rates similar to those seen with the first course of treatment, and there was no increase in adverse events or antigenicity to etanercept during the second round of treatment.³³




Figure 7




• Psoriatic arthritis. Treatment with 25 mg etanercept twice weekly produced significant reductions in the signs and symptoms of psoriatic arthritis; 59% of etanercept-treated patients achieved ACR 20 at week 12, and the effects were sustained through 48 weeks of treatment.³⁴

Snapshot of etanercept
Etanercept is a TNF-blocking agent that is effective in the treatment of psoriasis and psoriatic arthritis. The initial dose required to achieve maximal efficacy in psoriasis is twice as high as that required for efficacy in joint disease, but dosing can be stepped down in psoriasis patients after the first 3 months of treatment without loss of efficacy in approximately 75% of patients (although some may need the higher dose to maintain treatment benefits). Long-term studies of etanercept in psoriasis patients are still ongoing, but long-term studies in rheumatoid arthritis patients treated with the lower dose demonstrate a good safety profile with no evidence of long-term toxicity. The extensive use of etanercept in rheumatological disorders has revealed some rare but potentially serious problems (such as demyelinating disorders, lymphoma, and congestive heart failure) that may be associated with etanercept and suggest caution in patient selection and monitoring.

Future directions for etanercept research
The greatest need for more research in etanercept therapy is in its long-term use in psoriasis patients. There is a very large safety database for etanercept use in other disorders, but psoriasis patients are often treated with higher doses of etanercept and may have unique characteristics that cause them to respond differently in long-term therapy. It will also be important to investigate the efficacy, as well as the safety, of etanercept in long-term use in psoriasis.

Continued vigilance is needed regarding some of the rare, but potentially serious, problems that can arise during etanercept therapy. The occurrence of neurologic or cardiovascular problems during etanercept treatment seems to be rare, which makes it difficult to gather true incidence data in psoriasis patients. Consequently, all problems that do occur should be carefully documented and reported to the manufacturer and/or to MedWatch so that these phenomena can be better understood.