A User's Guide to the Field of Biologic Therapies

Biologic agents have been incorporated into the repertoire of psoriasis therapy with high frequency and success in recent years. Although results of therapy vary from patient to patient, biologics have introduced a new level of efficacy for patients with psoriatic disease. As physicians have gained more familiarity with prescribing and administering these agents, the landscape of available treatments has shifted and grown, evidenced recently by the withdrawal of efalizumab (Raptiva, Genentech) and the approval of golimumab (Simponi, Centocor) for psoriatic arthritis in April 2009.

Therefore, it is perhaps timely to take a closer look at the current slate of biologics for the treatment of psoriatic disease. Some of the agents discussed below have been approved and used for years, where others will likely be approved in a matter of months. Nevertheless, by situating key data for each of these agents and presenting them side-by-side, I hope to reveal key insights on each individual therapy and gain a broader perspective of biologics and psoriatic disease.

CLINICAL INSIGHTS
TNF inhibitors (discussed on the following pages) as a class are associated with an increased risk of infection. A black-boxed warning reminds physicians that patients who are prescribed these medications are at increased risk of serious infections. As a consequence, it is presently recommended that all patients be screened for tuberculosis prior to initiating therapy with one of these agents. This class of medications has also been associated with adverse outcomes in patients with heart failure and should be used in these patients only after consideration of other treatment options. Additionally, TNF inhibitors should not be used in cases of pre-existing central nervous system (CNS) disorders or those with a family history since they may increase patients risk of developing or worsening this type of disease.

ALEFACEPT
Alefacept is a dimeric fusion protein used to control inflammation in moderate-to-severe psoriasis with plaque formation, where it interferes with lymphocyte activation.

Mechanism of action. Alefacept consists of the extracellular CD2-binding portion of the human leukocyte function antigen-3 (LFA-3) linked to the Fc (hinge, CH 2 and CH 3 domains) portion of human IgG1. It inhibits the activation of CD2+, CD4+, and CD8+ T-cells, which stimulate hyperproliferation of keratinocytes.

Indication and use. Alefacept is indicated for the treatment of adult patients with moderate-to-severe chronic plaque psoriasis and who are candidates for systemic therapy or phototherapy. The recommended dose is 15mg once weekly as an intramuscular injection. The recommended regimen is a course of 12 weekly injections, after which retreatment with an additional 12-week course can be considered if CD4+ T lymphocyte counts are within the normal range, and a minimum of a 12-week interval has passed since the previous course of treatment. Data on retreatment beyond two cycles are limited, but appear safe.

As a monotherapy, alefacept often fails to yield comparable results to other biologic agents and systemic therapies. However, alefacept can be utilized in combination with other therapies and offers advantages in unique cases. For example, in one study, alefacept plus Narrowband UVB therapy helped to accelerate and improve the clearance of psoriasis,¹ and in another was used effectively in combination with topical corticosteroids.² For patients with psoriatic arthritis, alefacept may also prove an effective combination with methotrexate.³

Precautions and Side Effects. Known for its strong safety profile, alefacept has not been strongly linked to significant adverse events and is largely well-tolerated. Common adverse events observed in the first course of placebo-controlled clinical trials were pharyngitis, dizziness, increased cough, nausea, pruritus, myalgia, chills, injection site pain, injection site inflammation, and accidental injury. In the 24-week period constituting the first course of placebo-controlled studies, serious infections were noted at a rate of 0.9 percent patients treated with alefacept and 0.2 percent in the placebo group. In patients receiving repeated courses of alefacept therapy, the rates of serious infections were 0.7 percent and 1.5 percent in the second and third course of therapy, respectively.

As always with any immunosuppressive agents, it's important to monitor a patient's tolerance for the drug, as well as the symptoms of infection, allergic reaction, and malignancy.

ETANERCEPT
Etanercept is a fusion protein that binds to soluble TNFa and decreases its role in inflammatory disorders and autoimmune diseases, such as ankylosing spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, and rheumatoid arthritis.⁴

Mechanism of action. Etanercept is a fusion molecule produced through expression of recombinant DNA. It combines the soluble TNF receptor to IgG1. Since it is a fusion protein rather than a simple TNF receptor, etanercept has a greatly extended half-life in the bloodstream, and therefore a longer-lasting biologic effect than a naturally occurring TNF receptor.⁵

Indication and use. The recommended starting dose of etanercept for adult patients is a 50mg injected subcutaneously twice weekly (administered three to four days apart) for three months, followed by a reduction to a maintenance dose of 50mg per week. Etanercept is self-administered utilizing either pre-filled syringes or a "pen."

One of the more notable aspects is how well-tolerated etanercept is over time while maintaining strong efficacy. In one 2007 study, researchers reported improvements in physician- and patient-reported measures of psoriasis severity for up to 96 weeks of continuous etanercept therapy.⁶

When it comes to the relation of efficacy and the course of therapy, continuous etanercept treatment appears to provide greater sustained improvements in PROs than interrupted therapy.⁷ But it's worth noting that interrupting etanercept therapy, if needed, has predictable and manageable effects.⁸ Etanercept has also been shown to reduce disease severity in children and adolescents with psoriasis.⁹

Etanercept has been used effectively in combination with other systemic and non-systemic therapies. One of the more common combinations physicians rely on is a combination of etanercept and methotrexate. Trials evaluating this combination are limited for the treatment plaque psoriasis, but those conducted with psoriatic arthritis patients have yielded strong results.^10-11 In addition, a combined therapeutic regimen with etanercept 25mg once weekly and acitretin 0.4mg kg(-1) daily has been shown to be equally effective as etanercept 25mg twice weekly, and more effective than acitretin alone.¹² Additionally, in a smaller study, etanercept has been shown to treat palmoplantar psoriasis effectively.¹³ It may also significantly reduce joint pain and nail symptoms in psoriasis patients.¹⁴

Precautions and Side Effects. Etanercept is generally well-tolerated. Injections site reactions constitute a majority of adverse events, reported in approximately 37 percent of patients in clinical trials. These were mild to moderate (erythema and/or itching, pain, or swelling) and generally did not necessitate drug discontinuation.

The rate of serious infections in clinical trials has not increased in open-label extension trials and is similar to those observed in controlled trials. Serious infections experienced by etanercept-treated patients have included: cellulitis, gastroenteritis, pneumonia, abscess, tuberculosis and osteomyelitis. Rare reports of sepsis and death have been reported during post-marketing use of etanercept in patients with rheumatoid arthritis, some of which have occurred mere weeks after initiating treatment. Importantly, many patients who experienced these adverse events had underlying conditions (e.g., diabetes, congestive heart failure, history of active or chronic infections) in addition to their rheumatoid arthritis. Thus, obtaining a complete medical history from all patients both prior to starting therapy and at regular intervals while on chronic therapy is crucial. Finally, as with all biologics, there is a possible risk of malignancy in patients undergoing treatment with etanercept. It is therefore important to regularly monitor the patients for possible symptoms associated with malignancy as well as examine their skin for skin cancer.

INFLIXIMAB
Infliximab is a tumor necrosis factor (TNF) blocker currently approved for the treatment of psoriasis, psoriatic arthritis, Crohn's disease, ankylosing spondylitis, rheumatoid arthritis, and ulcerative colitis.

Mechanism of action. Infliximab is biologically engineered from human (75 percent) and mouse (25 percent) antibody molecules. It is a chimeric IgG1 monoclonal antibody that directly binds to both soluble and non-soluble TNF molecules in the blood and diseased tissue. Infliximab binds with great affinity to cell-bound and circulating TNFa, a pleiotropic proinflammatory cytokine that has local and systemic effects on a variety of cells and tissues.

Indication and use. For patients with psoriasis, the drug labeling indicates that 5mg/kg infliximab should be infused intravenously at weeks zero, two, and six, followed by eight to 12 week intervals thereafter, depending on the patient's response. In practice, some physicians have had success administering it every six to eight weeks.

Since its approval, infliximab has been known to provide rapid relief for psoriasis. The EXPRESS trials elucidated more details about efficacy of infliximab. Reich, et al.¹⁵ found that in some cases, patient response was seen as early as week two. By week six, the authors noted that significantly more infliximab patients had achieved a PASI 75 and PASI 90. Menter, et al.¹⁶ compared regular vs. on-demand maintenance regimens, finding that PASI responses were better maintained with continuous therapy compared with intermittent therapy. Infliximab has also been combined with Methotrexate therapy with generally high success in both psoriasis and psoriatic arthritis.¹⁷

Precautions and Side Effects. Infliximab like the other TNF inhibitors is associated with the risk of infection as was described earlier in this manuscript. The boxed warning serves to remind physicians that the risks of TB and serious infection are important to review with patients prior to initiating treatment. The risk of malignancy in psoriasis patients remains unknown. A small increase in malignancy rate has been seen in other indications.

Acute infusion-related reactions can be seen in patients taking infliximab and can include symptoms such as dizziness and headache, difficulty in breathing or swallowing, chest pain, swelling of face, lips, or hands, flushing, urticaria, and burning at the IV infusion site. These may be treated with antihistamines, or by reducing the rate of infusion. In a small number of patients, lupus-like symptoms and signs may occur. These include photosensitivity and joint and muscle pain (arthritis and arthralgias). Treatment should be stopped if these occur.

ADALIMUMAB
Similar to infliximab and etanercept, adalimumab binds to TNFa, which prevents it from activating TNF receptors. However, while infliximab is a mouse-human chimeric antibody, and etanercept is a TNF receptor-IgG fusion protein, adalimumab was constructed from a fully human monoclonal antibody.

Mechanism of Action. Adalimumab binds to TNF-a and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF-expressing cells in vitro in the presence of complement. Additionally, it modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 × 10-10 M).

Indications and Use. Adalimumab is approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, moderate to severe chronic psoriasis, and juvenile idiopathic arthritis. The initial dose is 80mg (two 40mg injections), followed by a 40mg dose one week later and 40mg doses every other week thereafter. Patients can self-administer adalimumab in pre-loaded syringes or in "pens" (i.e. the Humira Pen).

Adalimumab can be used alone or in combination with methotrexate or other DMARDs. As a monotherapy, it has been shown to be effective and well tolerated in patients with moderate to severe psoriasis.^18,19 It is also a reliable and well-tolerated therapy for patients with psoriatic arthritis when used in combination with methotrexate, as evidenced in a study that found through 48 weeks, psoriatic arthritis patients demonstrated improved joint and skin manifestations, reduced disability, and inhibited radiographic progression.²⁰ Due to its strong efficacy profile, patients also typically report significantly improved quality of life.²¹ Adalimumab can also be used in combination with phototherapy, topical treatments, and non-steroidal anti-inflammatory drugs.

Precautions and Side Effects. The most common side effects for adalimumab include upper respiratory infection, headache, abdominal pain, rash, injection site reactions, and urinary tract infections. These side effects are generally mild, occurring after the initial dose and diminishing over time. However, like with the others in this class, concerns for a link between adalimumab and TB have led to the FDA issuing a boxed warning. Patients therefore should be tested for latent TB infections. Also, other serious infections have been reported, again similar to those seen with the other TNF inhibitors.

GOLIMUMAB
Golimumab is a human monoclonal antibody for the treatment of moderately to severely active rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis. Approved in April 2009, golimumab is a once-monthly, patient-administered TNF-a therapy.

Mechanism of Action. Golimumab is a monoclonal antibody that blocks human tumor necrosis factor-a. It may improve these disease states by preventing or treating the contributing inflammation.

Indication and Use. Golimumab is approved as a 50mg subcutaneous injection once a month and is indicated alone or in combination with methotrexate for the treatment of adult patients with active psoriatic arthritis. It is available as a 50mg/0.5mL single-dose prefilled syringe or autoinjector.

Due to its recent entry on the market, it is not yet approved for psoriasis, and long-term data is non-existent. A phase 3 trial evaluating golimumab in the treatment of psoriatic arthritis showed that 50mg and 100mg through 24 weeks significantly improved signs and symptoms of active psoriatic arthritis with continuous treatment.²²

Precautions and Side Effects. The most common adverse reactions observed include upper respiratory tract infections, sore throat, nasal congestion, liver problems, redness at the site of injection, and high blood pressure.

Like with the other members of this class, there are reports of serious infections caused by bacteria, fungi, and viruses, including tuberculosis (TB) and histoplasmosis. Some of these infections have been fatal. Therefore, PPD screenings are essential before treatment. Moreover, patients should not start Simponi if they have any evidence of an active infection.

USTEKINUMAB
Ustekinumab (Stelara, Centocor) is a human anti-interleukin 12 (IL-12) and anti-interleukin 23 (IL-23) monoclonal antibody administered by subcutaneous injection. It is approved for moderate to severe psoriasis in Canada and Europe, and is pending approval in the US.

Mechanism of Action. Ustekinumab is designed to interfere with interleukins IL-12 and IL-23, naturally occurring proteins that are important in regulating the immune system. They are also believed to play a role in immune-mediated inflammatory disorders.

Trial Results. To date, the PHOENIX trials have revealed a number of clinical insights about the drug. In both the Phoenix I and Phoenix II clinical trials approximately two thirds of treated patients had an excellent clinical response to therapy.^23-24

Precautions and Side Effects. The most commonly reported adverse events associated with ustekinumab treatment in clinical trials were cough, arthralgia, injection-site reaction, and headache. Screening patients prior to initiating treatment and at regular intervals is also recommended with this therapy.

Clinical Viability. With a different mode of action to existing biologicals and a convenient dosing regimen (a maximum of four injections over 12 weeks), ustekinumab could provide dermatologists with another valuable treatment option for this chronic skin disorder.

CLINICAL INSIGHTS
Although the biological landscape continues to change, biologic agents provide physicians with a reliable canvas of therapies for psoriasis. With proper screening and monitoring, physicians can maximize the potential of these agents and achieve effective therapy for various manifestations of psoriatic disease.

Dr. Van Voorhees has served as a consultant, advisor or performed clinical trials for the following companies: Amgen, Abbott, Centocor, Incyte, Warner Chilcott, Connetics, Synta, Roche, Astellas, Bristol Myers Squibb, IDEC, VGX and Xtrac.

1. Legat FJ, et al. Narrowband UV-B phototherapy, alefacept, and clearance of psoriasis. 2007-08, Arch Dermatol., 143(8):1016-22
2. Langewouters AM, et al. The effect of topical corticosteroids in combination with alefacept on circulating T-cell subsets in psoriasis. 2007, J Dermatolog Treat., 18(5):279-85
3. Mease PJ, et al. Alefacept in combination with methotrexate for the treatment of psoriatic arthritis: results of a randomized, double-blind, placebo-controlled study. 2006-05, Arthritis Rheum., 54(5):1638-45
4. Braun J, et al (2007). "Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly". Rheumatology (Oxford) 46 (6): 999–1004
5. Madhusudan S, Muthuramalingam SR, Braybrooke JP, et al. (2005). "Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer". J. Clin. Oncol. 23 (25): 5950–9.)
6. Tyring S, et al. Long-term safety and efficacy of 50 mg of etanercept twice weekly in patients with psoriasis. 2007-06, Arch Dermatol., 143(6):719-26)
7. Gelfand JM, et al. Patient-reported outcomes and health-care resource utilization in patients with psoriasis treated with etanercept: continuous versus interrupted treatment. 2008-05, Value Health., 11(3):400-7
8. Gordon KB, et al. Clinical response in psoriasis patients discontinued from and then reinitiated on etanercept therapy. 2006, J Dermatolog Treat., 17(1):9-17
9. Paller AS, et al. Etanercept treatment for children and adolescents with plaque psoriasis. 2008-01-17, N Engl J Med., 358(3):241-51
10. Gotlieb A, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008 May;58(5):851-64.
11. Goldsmith DR, Wagstaff AJ. Etanercept: a review of its use in the management of plaque psoriasis and psoriatic arthritis. Am J Clin Dermatol. 2005;6(2):121-36
12. Gisondi P, Del Giglio M, Cotena C, Girolomoni G, Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24-week, randomized, controlled, investigator-blinded pilot trial. Br J Dermatol. 2008; 158(6):1345-9.
13. Bissonnette R, et al. Etanercept in the treatment of palmoplantar pustulosis. 2008-10, J Drugs Dermatol., 7(10):940-6
14. Luger TA, et al. Sustained improvement in joint pain and nail symptoms with etanercept therapy in patients with moderate-to-severe psoriasis. J Eur Acad Dermatol Venereol. 2009 Apr 23
15. Reich, et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet. 2005 Oct 15-21;366(9494):1333-5.
16. Menter AM, et al. A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2007 Jan;56(1):31.e1-15.
17. Warren RB, et al. Long-term control of recalcitrant psoriasis with combination infliximab and methotrexate. Clin Exp Dermatol. 2009 Apr;34(3):415-6.
18. Gordon KB, et al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. 2006-10, J Am Acad Dermatol., 55(4):598-606.
19. Menter, et al. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. 2007-10-11, J Am Acad Dermatol
20. Gladman, DD, et al. Adalimumab for long-term treatment of psoriatic arthritis: forty-eight week data from the adalimumab effectiveness in psoriatic arthritis trial. 2007-02, Arthritis Rheum., 56(2):476-88
21. Revicki, et al. Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: results from a 16-week randomized controlled trial in patients with moderate to severe plaque psoriasis. 2008-03, Br J Dermatol., 158(3):549-57
22. Kavanaugh A, et al. Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: Twenty-four-week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum. 2009 Apr;60(4):976-86.
23. Leonardi CL, Kimball AB, Papp KA, et al; PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1) [erratum in Lancet. 2008;371:1838]. Lancet. 2008;371:1665–1674.
24. Papp KA, Langley RG, Lebwohl M, et al; PHOENIX 2 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371:1675–1684