Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

17th Congress of the European Academy of Dermatology and Venereology

Paris, France / September 17-21, 2008

As described by Dr. Jean-Paul Ortonne, Department of Dermatology, Nice University Hospital, France, psoriasis is a life-long disease with a large impact on quality of life as well as potentially important comorbidities, including cardiovascular complications. Existing systemic therapies for psoriasis must often be administered intermittently and are limited by long-term safety concerns. Monoclonal antibody technology allows physicians to target specific components of the psoriatic disease process. The interleukin (IL) 12 and 23 pathway has been shown to be essential to the pathogenesis of psoriasis and represents a major systemic target in biologic therapy of this disease.

Targeting the Interleukin 12/23p40 Subunit

According to Dr. Jörg Christoph Prinz, Ludwig-Maximilians-University, Munich, Germany, there are now a number of treatments available that interfere with the pathogenesis of psoriasis and downregulate the inflammatory process. In psoriatic plaques, IL 12 and 23 are over-expressed, therefore representing a novel treatment target. “We have seen that interfering with IL 12/23 can lead to remissions in psoriasis patients, and this tells us that IL 12/23 clearly plays a central role in the pathogenesis of this disease,” he told delegates. “These two cytokines promote T-cell activation and differentiation, controlling inflammation and keratinocyte proliferation. We have seen that blocking IL 12/23 by neutralizing antibodies against the p40 subunit of those cytokines is highly effective in controlling disease activity in psoriasis.”

Two novel, fully human monoclonal antibodies, ustekinumab and ABT-874, have been designed and developed to bind specifically to the IL 12/23p40 subunit to help block those cytokines from activating T-cells known to be directly involved in psoriatic pathogenesis, making their mode of action unique compared with other currently available biologic therapies for psoriasis.

The PHOENIX Trials

Dr. Peter van de Kerkhof, Chair, Department of Dermatology, University Medical Centre St. Radboud, Nijmegen, The Netherlands, presented results on the phase III PHOENIX (Psoriasis Following Long-Term Extension) trials of ustekinumab.

PHOENIX 1 and 2 evaluated the efficacy and safety of ustekinumab in patients with moderate to severe plaque psoriasis. The primary outcome measure of both these trials was the proportion of patients achieving a Psoriasis Area and Severity Index (PASI) improvement score of at least 75% (PASI 75) from baseline after 12 weeks of treatment.

PHOENIX 1 and 2 randomized 766 patients and 1230 patients, respectively, to receive ustekinumab subcutaneous (s.c.) injections at doses of 45 mg (n=255 and 409) or 90 mg (n=256 and 411) at weeks 0 and 4 and every 12 weeks thereafter.

Dr. van de Kerkhof reported that week 12 PASI 75 responses from both PHOENIX 1 and 2 were 67.1% and 66.7% in the 45-mg treatment cohort and 66.4% and 75.7% in the 90-mg group vs. remarkably low response rates of 3.1% and 3.7% in the placebo groups (all P<0.001 vs. placebo) (Figure 1).

In PHOENIX 1, “With respect to the Physicians Global Assessment (PGA), 60% and 62% of patients reached clearing or minimal psoriasis in the 45-mg and 90-mg groups, respectively. Using the criterion of PASI 90, 42% and 37% reached that goal following the two injections of ustekinumab at weeks 0 and 4,” Dr. van de Kerkhof told delegates. PASI 75 responses for PHOENIX 1 and 2 were consistent to week 28 at about 70% and 79% for both 45-mg and 90-mg dosing schedules, respectively.

In PHOENIX 1, 255 patients initially given placebo at weeks 0 and 4 were crossed over to a first injection of ustekinumab at week 12, a second at week 16 and a third at week 28. Patients initially started on active treatment who achieved a PASI 75 at weeks 28 and 40 were re-randomized at week 40 to maintenance therapy or withdrawal from treatment until loss of response.

Figure 1.

Dr. van de Kerkhof reported that the interval of 12 weeks between maintenance doses appeared to be the most optimal regimen. “Maintenance treatment is effective with every-12-weeks dosing,” he emphasized, as PASI 75 response rates out to 76 weeks remained high, while response rates in patients switched to placebo decreased continuously with a median relapse rate (loss of PASI 75 response) of 15 weeks.

Safety data demonstrated no significant differences between active treatment and placebo in the long-term maintenance phase. The common adverse events were mild and included upper respiratory tract infections, nasopharyngitis and headache. Dr. van de Kerkhof, however, pointed out the higher rate of arthralgia in patients who interrupted active treatment and went on placebo. “This raises the question: what could ustekinumab actually do in psoriatic arthritis?”

He answered by reporting results of a phase II study in psoriatic arthritis patients treated with ustekinumab led by Dr. Alice Gottlieb, Tufts Medical Center, Boston, Massachusetts. The primary end point of an ACR 20 response at week 12 was achieved by a significantly greater proportion of ustekinumab-treated patients at 42.1% vs. 14.3% for placebo (P<0.001). “The same schedule as used in the first phase of psoriasis also in psoriatic arthritis can be effective,” he told delegates.

Dr. Kerkhof concluded that ustekinumab administered in 45 mg or 90 mg s.c. injections every 12 weeks was efficacious in moderate-to-severe psoriasis, “It provides a rapid and sustained PASI 75 response in the majority of patients, which can be maintained safely with as few as four injections per year.”

ACCEPT

According to Dr. Christopher Griffiths, Head, Greater Manchester Dermatology Centre, UK, “Direct comparisons of biologics one against the other are currently lacking and it is only by having this commonly used outcome measure, the PASI 75, that we are able [to compare studies].”

ACCEPT (A Study of the Safety and Effectiveness of CNTO 1275 [ustekinumab] Compared to Etanercept for the Treatment of Moderate to Severe Plaque Psoriasis) is the first study directly comparing biologic therapies for psoriasis.

According to Dr. Griffiths, the TNF-a antagonist etanercept was chosen because it is the most commonly used biologic agent in psoriasis and the benchmark against which others should be evaluated.

Investigators randomized patients to receive s.c. injections of ustekinumab 45 mg (n=209) or 90 mg (n=347) at weeks 0 and 4, or etanercept 5 mg twice weekly (n=347) through week 12. End points included the proportion of patients who achieved a PASI 75 response, PGA scores of “cleared” or “minimal” and PASI 90 response at week 12.

Preliminary data at 12 weeks demonstrated that in patients with moderate-to-severe psoriasis, both doses of ustekinumab demonstrated significantly superior response as measured by PASI 75 and 90 and PGA compared to etanercept twice weekly for 12 weeks. He concluded, “I believe that this head-to-head approach is going to be the gold standard for future studies and it has important clinical implications for management of severe psoriasis.”

Summary

Antibodies that target IL12/23 offer a promising new treatment option for moderate-to-severe psoriasis. Recently completed phase III studies have shown this strategy to be rapid, efficacious and safe over the long term.

To view the entire satellite symposium, visit https://www.eadv2008.info/archived_event and enter the password EADV2008

Note: At the time of printing, ustekinumab is not approved in Canada.