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FRONTLINE - Based on sessions from the 68th Annual Meeting of the American Academy of Dermatology (AAD)

Miami, Florida / March 5-9, 2010

Restoring Treatment Response in Psoriasis by Switching to Another Biologic

Editorial Overview:

Yves P. Poulin, MD, FAB, FRCPC

Centre dermatologique du Québec métropolitain, President, Canadian Dermatology Association, Associate Clinical Professor of Dermatology, Université Laval, Quebec City, Quebec

Psoriasis affects up to 3% of the general population, making it one of the most common immune-mediated disorders. Among several clinical phenotypes, chronic plaque psoriasis accounts for about 90% of cases (Schmitt et al. Br J Dermatol 2008;159:513-26).

For moderate-to-severe psoriasis, systemic therapies offer the best chance for clinically significant improvement. Multiple conventional systemic agents have demonstrated efficacy in psoriasis, most notably, methotrexate, which remains a mainstay of therapy even with the emergence of new approaches with biologics.

Improved understanding of the inflammatory cascade that drives psoriasis led to recognition of the central role that tumour necrosis factor-alpha (TNF-a) plays in pathogenesis. TNF-a inhibitors already demonstrated substantial efficacy in the treatment of rheumatoid arthritis and inflammatory bowel disease, and with the similar inflammatory pathway involved in psoriasis, they were a logical choice beyond conventional treatment.

TNF-a Inhibitor Efficacy

TNF-a inhibitors have demonstrated substantial efficacy in the treatment of psoriasis. For example, a randomized clinical trial involving 835 patients with chronic plaque psoriasis showed that 75.5% of patients treated with infliximab achieved at least 75% improvement in the Psoriasis Area and Severity Index (PASI 75) by week 10 vs. 1.9% for placebo (Menter et al. J Am Acad Dermatol 2007;56(1):31.e1-e15). Consistent with those results, two smaller trials demonstrated PASI 75 response rates of 80% and 88% vs. 3% and 6% for placebo, respectively (Reich et al. Lancet 2005;366:1367-74, Gottlieb et al. J Am Acad Dermatol 2004;51:534-42).

Two other TNF -a inhibitors, etanercept and adalimumab, also have shown efficacy in the treatment of psoriasis. In one representative trial of etanercept, patients treated with three different doses of the anti- TNF agent had PASI 75 response rates as high as 49%, compared with 4% for placebo at week 12 (Leonardi et al. N Engl J Med 2003;349:2014-22). Two randomized trials of adalimumab demonstrated PASI 75 response rates at week 16 of 71% and 79.6% vs. 7% and 18.9% for placebo, respectively (Menter et al. J Am Acad Dermatol 2008;58:106-15, Saurat et al. Br J Dermatol 2008;158:558-66).

In rheumatology clinical practice, patients who do not respond to an anti-TNF agent or lose response to the agent often are switched to another agent in the same class. Only recently the strategy of TNF switch has been evaluated in controlled clinical trials, but data reported to date, primarily from meeting abstracts, have shown that patients often respond to a second TNF -a inhibitor or even a third.

Few clinical trials have examined the potential to achieve or regain therapeutic response in psoriasis by switching anti-TNF agents, although the strategy is used fairly often in clinical practice. Evidence from autoimmune diseases other than psoriasis support transition among biologic agents, even when they are in the same class or have the same targets. Drug-specific antibodies or different mechanisms of delivery might create the potential for a new therapy to achieve or recapture therapeutic response.

Studies reported at the American Academy of Dermatology meeting provided new insights into the clinical potential of therapeutic switch with anti-TNF agents.

Recapturing Response: Evidence from PSUNRISE

In the PSUNRISE study (P3341), patients who had significant disease activity despite treatment with etanercept for =4 months were transitioned to infliximab two weeks after their last dose of etanercept. Transition followed two dosing regimens: three months of subcutaneous (s.c.) etanercept induction therapy with 50 mg twice weekly, followed by at least one month of maintenance therapy; or ongoing maintenance with 25 mg twice weekly or 50 mg once or twice weekly. Patients received 5 mg/kg infliximab infusions at weeks 0, 2, 6, 14 and 22.

The primary end point was the proportion of patients who achieved a physician global assessment (PGA ) score =1 (clear or minimal) at week 10 after receiving at least one dose of infliximab.

Investigators enrolled 217 patients, treated 215 and evaluated 211 for the primary end point. All patients had significant disease activity, defined as PGA =2. The study population was 64% male, had a mean age of 44, mean weight of 93.5 kg, mean body mass index of 31.4, mean psoriasis duration of 19 years and mean baseline PGA 2.8.

By week 10, primary analysis showed that 18% of patients had a PGA 0 (clear) and 47.4% had a PGA 1 (minimal), resulting in an overall response rate of 65.4%. Evidence of infliximab’s activity emerged within one week, when 14% of patients had a PGA 1 and 1% had a PGA 0. The proportion of patients who achieved PGA 0 continued to increase after week 10 and reached 27.5% at week 26. The proportion of patients with PGA 1 remained stable and was 44.9% at week 26.

Secondary end points of the trial included PASI 75 responses. While baseline PASI was not presented, 51.7% of patients had achieved a PASI 75 response at 10 weeks, increasing to 54.5% at 26 weeks. It must be noted that the median body surface area was at 11% at baseline compared to 29% for patients in the EXPRESS trial (Reich et al. Lancet 2005).

Two-thirds of patients had one or more adverse events, but the rate of serious adverse events was 3.7%. A third of the patients developed infections during treatment, most often respiratory tract infections (9.8%); only one infection was considered serious. Infusion reactions occurred in 5.6% of patients. Respiratory infection, arthralgia (8.8%), headache (6.5%) and nasopharyngitis (5.6%) were the only adverse events that affected at least 5% of patients.

At week 10, 2.8% of patients had withdrawn because of adverse events and another 2.8% because of lack of efficacy. At week 30, adverse events had led to withdrawal of 6% of patients and lack of efficacy to a withdrawal rate of 5.1%.

Supportive Evidence

About 50% of patients with psoriasis have psoriatic In patients with psoriasis that achieved suboptimal response to etanercept, methotrexate or narrowband ultraviolet (UV-B) phototherapy, Strober et al. (P3306) examined the safety and efficacy of transition to adalimumab.

Patients transitioned from etanercept had a PGA of mild or worse after at least 6 months of therapy or documented deterioration of efficacy after 3 months of treatment. The methotrexate group had a PGA of mild or worse after at least 4 months of therapy. The phototherapy patients had a PGA of moderate or worse after at least 2 months of light treatment.

Patients initially treated with etanercept had a washout period of 11 to 17 days. The other two groups had washout periods of 4 to 10 days. Treatment with adalimumab began with 80 mg s.c. at baseline, followed by 40 mg every other week from week 1 through week 15.

The primary efficacy end point was PGA 0-1 at week 16. Secondary end points included the proportion of patients who had at least 1-grade improvement in PGA from pre-washout to 16 weeks and improvement in PASI.

The analysis included a total of 152 patients: 82 previously treated with etanercept, 41 with methotrexate and 29 with phototherapy. Of 136 patients who completed the study, 73 were in the etanercept group, 39 in the methotrexate group and 24 in the phototherapy group.

After 16 weeks of treatment with adalimumab, 52% of the patients overall had achieved a PGA 0-1. Broken down by prior treatment, 48.8% of the etanercept group achieved a PGA 0-1, 61% of the methotrexate group and 48.3% of the phototherapy group. Evidence of substantial improvement emerged as early as 4 weeks after the start of therapy.

Three-fourths of the entire patient population had a least one grade improvement in PGA by week 16, and the proportion in each subgroup was similar. Mean PASI score decreased from about 10 at baseline to about 5 at week 16 and was somewhat lower in the methotrexate group.

Investigators reported that 55% of patients had one or more adverse events, the most common being infection (21.7%). Serious adverse events occurred in 3.3% of patients, including one serious infection. One patient withdrew from the study because of an adverse event.

The IL-12/23 Inhibition Option

In contrast to TNF -a inhibitors, ustekinumab inhibits interleukins 12 and 23 (IL -12/23), two cytokines that play a key role in the immunopathogenesis of psoriasis.

In a randomized clinical trial, the agent demonstrated superior efficacy compared with etanercept in patients with plaque psoriasis (Griffiths et al. N Engl J Med 2010;362:118-28).

The agent’s activity in patients who achieve inadequate responses to a TNF -a inhibitor remained unclear. To that end, Griffiths et al. (P3357) in the randomized comparison of etanercept and ustekinumab evaluated the latter agent’s efficacy in 50 patients who did not achieve a PGA 0-1 with high-dose etanercept 50 mg twice a week and were crossed over to ustekinumab 90 mg injections on week 0 and 4.

Compared with patients who responded to etanercept, those who proved refractory were heavier (99.3 kg vs. 89.4 kg), were more likely to have PGA scores of marked or severe (64.0% vs. 39.2%), were more likely to have been treated with other biologic therapy (26.0% vs. 9.4%), and had higher rates of intolerance or contraindications to two or more conventional systemic psoriasis therapies.

Patients crossed over to ustekinumab after week 12 received 90-mg injections of the IL -12/23 inhibitor at weeks 16 and 20. At 24 weeks (12 weeks after crossover), 48.9% of the patients achieved a PASI 75 response or better, including 23.4% who had PASI 90 responses. Additionally, 70.2% of the patients achieved a PGA =2 (cleared, minimal or mild) and 40% achieved a PGA =1.

Among a total of 347 patients treated with etanercept in the trial, 79.3% had one or more adverse events. After crossover to ustekinumab, 64.7% of those patients reported at least one adverse event. Serious adverse events occurred in 3.5% of patients before crossover and 3.4% after. Rates of discontinuation because of adverse events were 3.2% and 0.7% before and after crossover, respectively.

Infection was the most common category of adverse event before and after crossover. Among individual adverse events, the most common before crossover were nasopharyngitis (15%), upper respiratory infection (11.2%), headache (11.8%) and injection-site reactions (24.8%). After crossover to ustekinumab, the most common adverse events were nasopharyngitis (12.9%), upper respiratory infection (11.9%), headache (3.1%) and injection-site reactions (1.7%).

Summary

The three studies summarized above provide data on the use of additional biologic therapy after suboptimal response to etanercept. The trial results cannot be compared directly, and the studies differed in some aspects of design and protocol. Those limitations notwithstanding, the studies demonstrated the feasibility and potential benefits of treatment with a biologic agent after failure of a first biologic agent, even when the two agents are in the same class.

In the infliximab study, 73% of patients achieved a PGA 0-1 (clear or minimal) after 10 weeks, following lack of satisfactory response to at least four months of treatment with etanercept. In the adalimumab study, 49% of patients achieved PGA 0-1 after 16 weeks, following inadequate response to etanercept. The ustekinumab study showed that 40% of patients achieved a PGA 0-1 at week 12, following suboptimal response to 12 weeks of treatment with high-dose etanercept.

The data do not carry the weight of a randomized, blinded clinical trial of different therapies. However, they do provide clinical results that practicing physicians can take into consideration in the management of patients with psoriasis.

P3306 Transitioning Psoriasis Patients to Adalimumab Following a Suboptimal Response to Etanercept, Methotrexate, or Phototherapy: Efficacy and Safety Results from an Open-Label Study

B. Strober, Y. Poulin, F. Kerdel, R.G. Langley, A. Menter, K.A. Papp, Y. Gu, M. Okun

The study addressed the efficacy and safety of immediate transition to adalimumab therapy for psoriasis treatment in patients experiencing a suboptimal response to prior therapy with etanercept (ETN ), methotrexate (MTX), or narrow-band ultraviolet B (NB -UVB) phototherapy.

In the 16-week, open-label, phase III b study, patients received an initial s.c. dose of adalimumab 80 mg at week 0, followed by 40 mg every other week beginning at week 1 and through week 15.

Primary efficacy end point

• Percentage of patients achieving a PGA of “Clear” or “Minimal” (PGA 0/1) at week 16

Secondary end points

• Proportion of patients achieving at least one grade of improvement in PGA (relative to screening, last evaluation before washout) and the
verity Index (PASI )

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Key Points

• A bout half of patients had clinically meaningful improvement with adalimumab after suboptimal response to etanercept, methotrexate or phototherapy.

• Substantial improvement occurred as early as 4 weeks in some patients.

• Transitioning was associated with acceptable safety and a low risk of disease flare.

Comments by Dr. Poulin: The results demonstrated that patients with difficult-to-treat psoriasis can be transitioned successfully from conventional systemic therapy and light therapy, as well as biologic therapy that produced an inadequate response. Notably, patients discontinued existing therapy abruptly and had a brief washout period before initiating biologic therapy. The study also showed that many patients will have substantial improvement within a month after starting the transition.

P3357 Ustekinumab Treatment in Patients with Moderate-to-Severe Psoriasis who are Nonresponders to Etanercept: Results from a Phase 3 Clinical Trial

C.E.M. Griffiths, B.E. Strober, N. Yeilding, A. Menter

To evaluate the clinical response to ustekinumab in patients with moderate-to-severe psoriasis who have
mage.php?id=3947" />actory to etanercept therapy (nonresponders) in a phase III trial.

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Key Points

• Both doses of ustekinumab resulted in significantly higher response rates compared with high-dose etanercept.

• The IL -12/23 inhibitor demonstrated substantial activity in patients with etanercept-refractory psoriasis.

• No increase in adverse events or new safety concerns occurred after the transition from etanercept.

Comments by Dr. Poulin: Because ustekinumab targets a different component of the inflammatory cascade, a rationale existed for transitioning patients who had inadequate response to a TNF -a inhibitor. Results of this study provide objective short-term evidence of achieving a PGA =1 in a substantial proportion of patients. The safety data offer reassurance that transition to an IL -12/23 inhibitor can occur with no increased risk to the patient or tolerability issues.

P3341 Infliximab Therapy in Psoriasis Patients Previously Treated with Etanercept: Final Efficacy and Safety Results from a Multicenter, Prospective Study

A.B. Gottlieb, R. Kalb, A. Blauvelt, M. Heffernan, H. Sofen, J. Wang, S. Calabro, U. Kerkmann, M. Chevrier

Development of drug-specific antibodies or the difference in delivery (i.e., weight-based vs. fixed/tiered dose strategies, intravenous delivery vs. s.c. delivery affecting CMax/T1/2) may play a role in allowing a new therapy to induce or recapture a previous response. Addition of concomitant therapies may further result in increased efficacy by modulating renal clearance or formation of new anti-drug antib
mage.php?id=3951" />gn: Patients inadequately responding to etanercept therapy for =4 months were transitioned to infliximab 5 mg/kg two weeks after their last etanercept dose.

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Key Points

• Two-thirds of patients achieved PGA 0-1 with infliximab after inadequate response to etanercept.

• The majority of patients responded within 6 weeks.

• PGA and PASI responses were durable through 26 weeks.

• No new safety issues were reported.

Comments by Dr. Poulin: The results support the practice of transitioning patients to a different biologic agent after inadequate response to initial biologic therapy. Because anti-TNF agents differ mechanistically and pharmacokinetically, failure of one agent in the class does not foretell failure of the entire class. Moreover, in this population of biologic-experienced patients, treatment with infliximab led to response rates comparable to those seen in some trials of biologic-naive patients.