Etanercept (Enbrel®) – An Update

B. Goffe MD
Department of Dermatology, University of Washington Medical School, Seattle, WA, USA

ABSTRACT

Etanercept is a tumor necrosis factor antagonist with anti-inflammatory effects. It is currently approved in the US for psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis and juvenile rheumatoid arthritis. Clinical trials have shown this agent to have an excellent safety profile and to be well tolerated by both adult and pediatric patients.
Key Words: etanercept, Enbrel®, psoriatic arthritis, TNF-alpha, psoriasis

Etanercept (Enbrel®, Amgen) is a recombinant human protein with anti-inflammatory properties that was the first approved treatment for psoriatic arthritis by the US FDA in January 2002. It was approved by TPP Canada in January 2004 for the same indication.^1-3 In May 2004, the US FDA approved this drug for the treatment of adult patients with chronic moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. In September 2004, the European Union approved it for the treatment of adult patients with moderate-to-severe plaque psoriasis who failed to respond to, or have a contraindication to, or are intolerant of other systemic therapies. Also in September 2004, the US FDA approved a new dosing form: a 50mg/ml prefilled syringe, which will allow most patients to take only one injection per week instead of two. Additional indications for etanercept include the treatment of rheumatoid and polyarticular-course juvenile rheumatoid arthritis (RA and JA respectively), and ankylosing spondylities. In RA the clinical responses to etanercept have been maintained for up to 7 years in clinical trials.⁴

Tumor necrosis factor (TNF) is a proinflammatory cytokine that has been strongly implicated in the pathogenesis of psoriasis and psoriatic arthritis, and plays a key role in the activation of innate and acquired immune responses. An inappropriate production of this cytokine is seen in psoriasis and psoriatic arthritis, which can lead to chronic inflammation, tissue damage and excessive keratinocyte proliferation. The downstream effects of excessive TNF production on various cell types and the clinical manifestations relevant to psoriasis and psoriatic arthritis are summarized in Table 1. Currently there are three TNF-alpha inhibitors available in the US – one receptor fusion protein (etanercept), and two monoclonal antibodies (infliximab and adalimumab).

Table 1: Effects of Excessive TNF Production on Various Cell Types*

*Reprinted with permission from the Journal of the American Academy of Dermatology, V49(2 suppl):S105-S111. Goffe B, Cather C: “Etanercept: An Overview,” © 2003 American Academy of Dermatology.

Mechanism of Action

Etanercept inhibits TNF activity by competitively binding to it and preventing interactions with its cell surface receptors. Elevated levels of TNF have been found in psoriatic skin lesions, and in synovial explants and fluid from patients with psoriatic arthritis.^5-7 Furthermore, TNF levels in the serum of patients with plaque psoriasis,⁸ and in blister fluids of involved psoriatic skin⁹ have also been shown to be higher than in those of controls. These values were significantly correlated with the psoriasis area and severity index (PASI) scores, and TNF levels were reduced in association with clinical resolution after effective treatment.⁸

The production of chemokines, and the expression of adhesion molecules by keratinocytes and vascular endothelial cells can be stimulated by TNF produced within psoriatic lesions. These signals then cause recruitment of additional inflammatory cells into the plaque. Krueger suggests that TNF may function as part of a positive feedback loop, which acts to amplify and sustain the inflammatory process within psoriatic plaques.¹⁰ Biologic responses that are induced or regulated by TNF are modulated by etanercept. It may, therefore, serve to reduce inflammation within plaques by breaking this cycle.

Clinical Studies

A 24-week, multicenter, double-blind, randomized, placebo-controlled, phase III trial studied etanercept as a monotherapy in moderate-to-severe psoriasis. Six-hundred-fifty-two patients with chronic, stable plaque psoriasis over ≥10% of their body surface area who had previously received or been candidates for phototherapy or systemic psoriasis therapy were enrolled. All systemic psoriasis therapies were discontinued within 4 weeks of the first dose of the study drug.¹¹

Patients received 50mg etanercept subcutaneously (SC) twice weekly (n=164), 25mg etanercept SC twice weekly (n=162), 25mg etanercept SC once weekly (n=160), or placebo SC twice weekly (n=166). Forty-nine percent of patients in the 50mg etanercept twice weekly group achieved at least a 75% improvement in the PASI score (PASI 75) at 12 weeks, compared with 4% of placebo-treated patients (p<0.001). Efficacy continued to improve with longer treatment: 59% of the etanercept 50mg twice weekly patients reached PASI 75 at 24 weeks of treatment. Statistically significant improvements in patient global, physician global, and quality of life as assessed by the Dermatology Life Quality Index (DLQI) confirmed the efficacy of etanercept therapy. Etanercept was well tolerated.

In another phase III monotherapy trial,³ 46% of patients receiving etanercept 50mg twice weekly achieved >PASI 75 at 12 weeks, compared with 3% of placebo-treated patients (p<0.0001). The majority of patients who achieved a PASI 75 in the 50mg biweekly arm continued treatment in an open-label extension where their etanercept dose was reduced to 25mg biweekly. At week 24, 77% had maintained their PASI 75 response using half of the original dose.

Etanercept in Psoriatic Arthritis

For adults with psoriatic arthritis and/or rheumatoid arthritis, the recommended dose of etanercept is 50mg administered SC once weekly using a 50mg/ml single-use pre-filled syringe.³ It may be used as monotherapy or concomitantly with methotrexate (MTX).

In a phase II, randomized, double-blind, placebo-controlled 12-week study, the efficacy and safety of 25mg twice-weekly subcutaneous injections of etanercept or placebo was assessed in 60 adult patients with psoriatic arthritis.¹ The study endpoints for psoriatic arthritis included the proportion of patients who met the Psoriatic Arthritis Response Criteria (PsARC) and American College of Rheumatology 20% criteria (ACR20) for improvement in the number of tender and swollen joints, as well as patient and physician assessments. The endpoints for psoriasis were a 75% improvement in the PASI score, and improvements in prospectively identified individual target lesions (≥2cm in diameter). The etanercept-treated group had statistically better outcomes for all clinical psoriatic arthritis endpoints. At 12 weeks, 87% of the etanercept-treated patients achieved the PsARC compared with 23% of patients receiving placebo (p<0.0001). The ACR20 was achieved by 73% of etanercept and 13% of placebo treated patients (p<0.0001).¹

Etanercept also improved the psoriasis skin lesions in this trial. The median target lesion response was 50% in the etanercept group compared with 0% in the placebo group (p=0.0004). There were 19 patients in each treatment group who met the criterion of ≥3% of body surface involvement and were eligible for evaluation for psoriasis using the PASI score. At 12 weeks, 26% of the etanercept, and 0% of the placebo-treated patients had achieved a 75% improvement in the PASI (p=0.0154).¹

An open label extension of this study demonstrated that treatment with etanercept allowed statistically significant reduction of concomitant MTX and/or steroid doses, and discontinuation of MTX and/or steroids in 25% and 44% of patients respectively.¹²

The results of this study were confirmed in a larger, 205 patient, multicenter, randomized, double-blind, placebo-controlled phase III trial of the efficacy and safety of etanercept in psoriatic arthritis.² Arthritis was significantly improved with etanercept treatment. ACR 20 was achieved by 59% of the etanercept group and 15% of the placebo group at 12 weeks (p<0.0001). Significant improvement in arthritis was maintained with continued etanercept treatment through the end of the study at 24 weeks. Results from the subset of patients who were evaluated using PASI showed a median improvement of 47% in patients receiving etanercept while a median 0% improvement was seen in those receiving placebo (p<0.0001).¹²

Etanercept Administration

Etanercept is supplied as a lyophilized powder (25mg to a vial) which requires reconstitution with sterile bacteriostatic water, which is also included. The administration is similar to that of insulin or SC methotrexate and can be easily taught to patients in a dermatology office setting. All patients are required to have regular follow-up visits while taking this medication. Ethanercept is now also available as a 50mg/ml single-use prefilled syringe. Prior to therapy, lab work that includes a baseline HIV, hepatitis panel, tuberculin skin test, ANA, comprehensive metabolic panel, and a complete blood count is reccomended. Thereafter, lab work may be done when deemed necessary. During therapy, patients are not allowed to be immunized with live virus vaccines. Etanercept may safely be given to patients who are already receiving MTX, as per the package insert. The cost for a 4-week supply of medication is approximately $1,100.00 USD.

Safety

Klareskog, et al. reported results of a long-term safety study of etanercept in 2,054 patients from North America and Europe.¹³ In the long-term follow-up group, the rates of infection requiring hospitalization or intravenous antibiotics were 0.04 events per patient-year, which is comparable to the rates seen in the placebo-control group during the double-blind portion of the trials.

However, it should be noted that postmarketing reports have included accounts of serious infections and sepsis, including fatalities with the use of etanercept. Even so, in the arthritis clinical trials, numerous patients were on concomitant methotrexate and/or prednisone without any increased risk of infection. Caution should be used when considering etanercept for patients with a history of recurring infections, and etanercept should not be administered to patients with sepsis or active infections, including chronic or localized infections.³ Patients who are on concomitant immunosuppressive therapies, or patients who may be predisposed to infections may have a greater risk of infection when they are given etanercept.

Patients who have had a significant exposure to varicella and have no immunity to this condition should temporarily discontinue etanercept, and prophylactic varicella zoster immune globulin should be considered.³

Rare reports of new onset or exacerbation of central nervous system demyelinating disorders, and pancytopenia in patients treated with etanercept have been noted by postmarketing surveillance. Consequently, caution should be exercised when considering the use of etanercept in patients with preexisting or recent-onset central demyelinating disorders. Discontinuation of etanercept therapy should be considered in patients with confirmed significant hematological abnormalities.³

Additionally, 11% of patients in clinical trials who were treated with etanercept developed a new positive ANA titer of 1:40 or greater, compared to 5% of patients who were in the placebo group. The development of anti-dsDNA antibodies was also higher in patients treated with etanercept when compared to those treated with placebo (15% and 4% respectively). Cases of drug-induced systemic lupus and subacute cutaneous lupus have been reported in the literature.^14,15 After discontinuation of etanercept these conditions resolved.

The US FDA pregnancy rating for etanercept is category B. However this rating was made based on results of developmental toxicity studies of etanercept performed in rats and rabbits. There have been no studies in pregnant women and, therefore, etanercept should be used during pregnancy only if clearly needed. It is not known if etanercept is excreted in human milk or absorbed systemically after ingestion. A decision to discontinue nursing or to discontinue etanercept should be made by nursing mothers.³

Adverse Events

In controlled trials, the only adverse event that occurred significantly more frequently in patients treated with etanercept compared to placebo was mild-to-moderate injection-site reactions, e.g., erythema and/or itching, pain, or swelling (see Table 2). These reactions tended to occur in the first month, subsequently decreased in frequency, and did not generally result in discontinuation of the drug.¹¹ Application of cool compresses and 1% hydrocortisone ointment are helpful to alleviate discomfort associated with injection-site reactions.

Conclusion

Clinical trials have demonstrated consistent efficacy for etanercept in the treatment of inflammatory diseases such as psoriasis, psoriatic arthritis, RA, and JRA, and research on the potential future use of this agent in other inflammatory diseases is ongoing. The rapid and significant clinical responses to etanercept highlight the central role of TNF in contributing to the pathology of these diseases, as well as etanercept’s potent inhibitory effects. Etanercept is well tolerated by both adult and pediatric patient populations, and long-term data on the use of etanercept have demonstrated an excellent safety profile.

Dr. Goffe has had research funded by Amgen, Biogen, Genentech and Centocor, and he has performed various paid consulting and speaking functions.

References

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