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Published on 16 January 2009

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Ustekinumab in the treatment of moderate-severe psoriasis

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Ustekinumab is a human monoclonal antibody that targets interleukins 12 and 23. With its novel mechanism of action, the drug could be an important option for patients with moderate-severe psoriasis

George M Lewitt
BS

Central Dermatology
St Louis
Missouri
USA

Craig L Leonardi
MD

Clinical Professor of
Dermatology
Saint Louis University
School of Medicine
St Louis
Missouri
USA

Based on clinical trial results, interleukins 12 and 23 have recently been shown to play an important role in the pathophysiology of psoriasis. Ustekinumab, a human monoclonal antibody directed against these targets, has been submitted to the EMEA and US-FDA for the treatment of psoriasis with decisions expected this year. The impressive efficacy, safety and unusual infrequent dosing regimen of
ustekinumab make this drug an attractive option for both patients and the dermatologists who treat them.

Introduction
Psoriasis is the most common immune-mediated skin disease, affecting an estimated 2% of the population. This chronic, genetic autoimmune disorder is characterised by recurrent exacerbations and remissions that can be emotionally and physically devastating.

The majority of patients have limited psoriasis and are well served by a variety of topical medications containing glucocorticosteroids, vitamin A analogues, vitamin D analogues, or combinations of these. However, a third of patients with psoriasis have moderate–severe disease, which in research trials is usually defined as involving ≥10% body surface area. Patients with moderate-severe disease are thought by most dermatologists to be beyond topical therapy and instead require
a systemic approach to control their psoriasis. Lastly, some patients are thought to have moderate–severe psoriasis if highly sensitive areas (eg, scalp, hands, feet, genitalia, face) are the only sites involved.[1]

In addition to skin findings, psoriasis is associated with several comorbid conditions and diseases. Among those with moderate–severe disease, a third will develop psoriatic arthritis, a debilitating and mobility–reducing condition affecting the tendons and joints. Patients with psoriasis also have a higher incidence of the metabolic syndrome which includes arterial
hypertension, dyslipidaemia and insulin resistance. In addition, they are more likely to be obese, clinically depressed and engage in unhealthy behaviours such as tobacco and alcohol use. Recently, the presence of severe psoriasis has been found to be associated with increased risk of myocardial infarction and overall mortality.[2] These observations suggest that psoriasis
is a systemic inflammatory process that could involve more than just the skin and joints.

In the past, treatment of moderate–severe psoriasis was limited by practical considerations (eg, ultraviolet phototherapy) and by drug–related end organ toxicities (eg, methotrexate, cyclosporine, oral retinoids, 6-thioguanine, hydroxyurea and fumaric acid esters). In response, a variety of intermittent and rotational treatment schemes emerged, usually in an attempt to limit exposure to one side–effect profile of one treatment by moving to another. Young patients requiring decades of care were rarely well served by these strategies.

In the latter half of the 1980s, the working hypothesis for the pathogenesis of psoriasis evolved from that of a keratinocyte (skin cell) disorder to one involving immune system dysregulation. With this new understanding has come a variety of biologic drugs that target specific sites in the inflammatory cascade.

Currently, psoriasis is best explained as an immune system dysfunction in genetically susceptible patients, resulting in activation of T lymphocytes located in skin, joints and perhaps other tissues, resulting in the release of inflammatory cytokines. In the last ten years, a variety of biologic therapies targeting specific steps in the inflammatory cascade have been tested, with some showing great promise and gaining approval by the EMEA and/or US–FDA. The current repertoire of biologic therapies can be divided into two categories – those blocking T-cell activation and those binding cytokines.

Ustekinumab as a potential treatment for moderate–severe psoriasis
Ustekinumab was developed by Centocor as an antibody targeting the cytokines IL12 and IL23.[3] These
cytokines play a major role in regulating the Th1 and Th17 inflammatory pathways, respectively, and ustekinumab is expected to have utility in a variety of disease states such as psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn’s disease, ulcerative colitis and others.

Like all trials evaluating a potential treatment for moderate–severe psoriasis, the ustekinumab trial used the Psoriasis Area and Severity Index (PASI ) to assess response. PASI is a semi-quantitative score, ranging from 0 to 72, and accounts for area, redness, thickness and degree of scale in the involved areas. Given the fact that patients enter trials with a range of PASI , both the US-FDA and the EMEA look at the relative change of PASI in each patient and consider a 75% reduction of PASI at endpoint compared to that at baseline (PASI – 75) as a primary measure of success.

Phase 3 trials
Two ustekinumab phase II trials were conducted in the US,[4] and in the US, Canada and Europe.[5] Both studies were similar, involving a placebo, ustekinumab (45 mg) and ustekinumab (90 mg) in the first 12 weeks, with extension studies scheduled to be carried out for a total of five years. Doses were administered on weeks zero, four and every 12 weeks thereafter. Using a conservative analysis (intent-to-treat nonresponder imputation), both of the ustekinumab low- and highdose arms achieved statistical significance at endpoint
(week 12), and showed continued improvement to 70% and 80% PASI-75, respectively, over an additional 28 weeks. The maintenance of this level of clearing with q12 week dosing is unprecedented.

Adverse effects within treatment groups were captured throughout the trials. During the placebo-controlled portion of the trial (initial 12 weeks), the rates and types of adverse events and laboratory abnormalities were very comparable between patients receiving ustekinumab 45 mg, ustekinumab 90 mg and placebo (Figure 1).

[[HPE41.14]]

As can be seen, the most common were nasopharyngitis, upper respiratory tract infections (URTI) and headache. In this trial, the overall rates of infection were similar to placebo (26.7%), ustekinumab 45 mg (31.4%) and ustekinumab 90 mg (25.9%). There were no opportunistic infections, malignancies, strokes or myocardial infarctions during this relatively short period.

Of particular interest, 68 patients with newly diagnosed latent tuberculosis (TB) were allowed into the trials if appropriate antituberculosis therapy had been initiated. After one year of the trial, none of these patients had developed active TB.

Clinical significance
All of these results hold great relevance and promise for clinical practice. Based on our current understanding, ustekinumab should be considered a first line biologic therapy for treating moderate-severe psoriasis. Other than an annual age-appropriate physical exam, it is unclear whether any additional tests will be clinically important or even be required by the regulatory authorities. Given its prolonged dosing interval, high efficacy and apparent endurance, ustekinumab could reduce some of the costs associated with inpatient and outpatient management of these patients.

A few caveats could limit or delay the drug’s use in clinical practice. First, there is some concern regarding patient management when using a new drug on a q12 week dosing schedule. The FDA is considering a proposal to make ustekinumab an in-office administered drug to ensure compliance and safety monitoring on a quarterly schedule.

Although there is a favourable efficacy-to-risk ratio, only 3,000 patients have been studied to date for roughly one year. Centocor is committed to long-term follow-up with data being captured in a maintenance study that will extend the data to a total of five years.

Lastly, the utility of ustekinumab in treating psoriatic arthritis was explored in a small phase 2 trial. Although the results were statistically significant, they were not as robust as those seen using previously approved biologic therapies. At the time of writing, it is unclear whether Centocor will choose to develop this indication.

The future of ustekinumab is bright. With its novel mechanism of action, the drug could be an important option for high-need patients who have failed other systemic and/or biologic therapies. With its profound effect on the IL12 pathway (T1 cytokine profile), there is a possibility for improved outcomes in psoriasis patients with coronary artery disease and the metabolic syndrome. And it has highlighted the importance of the IL23 pathway (T17 cytokine profile). Currently, psoriasis trials are underway using anti-IL17 and anti-IL22 antibodies to further explore this hypothesis.

Conclusion
In summary, ustekinumab is a fully human monoclonal antibody that is subcutaneously administered every 12 weeks. The drug is fast acting, with 70–80% of patients achieving durable PASI -75 over a 28-week period. The drug is well tolerated and, to date, appears to have an excellent safety profile. Ustekinumab has been submitted to the EMEA and the US-FDA, and upcoming decisions are expected by the last quarter of 2008.

References
1. Sterry W, Barker J, Boekhncke WH, et al. Biological therapies
in the systemic management of psoriasis: International
Consensus Conference. Br J Dermatol 2004;151(Suppl 69):3-17.
2. Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial
infarction in patients with psoriasis. JAMA  2006;296(14):1735-41.
3. Krueger GG, Langley RG, Leonardi CL, et al. A human interleukin-12/23 monoclonal antibody for the treatment of
psoriasis. N Engl J Med 2007;356:580-92.
4. Leonardi CL, Kimball AB, Papp K, et al. Efficacy and safety of
ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized double-blind, placebo-controlled trial (PHOENIX 1). Lancet
2008;371:1165-74.
5. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety
of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from
randomized, doubleblind, placebo-controlled trial (PHOENIX 2). Lancet 2008;371:1675-84.



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