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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.

PHYSICIAN PERSPECTIVE Viewpoint based on presentations during Dermatology Update 2009

Montreal, Quebec / March 25-28, 2009

Reviewed and edited by:

Neil H. Shear, MD, FRCPC

Chief of Dermatology, Professor of Medicine, Pharmacology, Pediatrics and Dermatology, University of Toronto

Head of Dermatology, Sunnybrook Health Sciences Centre, Toronto, Ontario

Addressing Treatment Barriers

An increasing body of evidence supports the use of systemic therapies for moderate to severe psoriasis. Interestingly, a recent survey of US dermatologists determined that about 40% of patients with severe disease receive monotherapy with a topical agent (Patel et al. J Am Acad Dermatol 2008;58(6):964-9). A separate patient survey found that up to 60% of individuals with severe psoriasis were receiving topicals alone and about one in three individuals was receiving no therapy at all (Horn et al. J Am Acad Dermatol 2007;57(6):957-62). Such statistics may help explain why a substantial proportion of individuals with psoriasis are dissatisfied with their treatment and why psoriasis continues to engender poor quality-of-life scores despite the extensive armamentarium available (Stern et al. J Investig Dermatol Symp Proc 2004;9(2):136-9).

There remain numerous barriers to successful psoriasis treatment. These may include physicians’ inadequate assessment of disease severity, lack of familiarity with consensus recommendations or treatment guidelines (American Academy of Dermatology guidelines for the use of biologic therapies: Menter et al. J Am Acad Dermatol 2008;58(5):826-50 – Canadian guidelines are expected shortly), or reluctance to prescribe potent agents due to the perceived time commitments required or concerns about long-term safety. Some clinicians are ill-informed about contemporary therapies or have received insufficient instruction in their use to be comfortable in prescribing them. For patients with psoriasis, resignation (“I just have to live with this”), fear of side effects from medications and third-party payment issues may constitute important hurdles.

Because effective treatment of psoriasis improves the patient’s overall health, happiness and ability to function, physicians should make the effort to eliminate any barriers they can. A comprehensive assessment can help properly define disease severity and ensure the patient’s condition is not underestimated or trivialized. Treatment need not be stepwise: in other words, the patient should not have to go through failure of a mild or topical therapy with a projected low likelihood of success before a more potent modality is employed. Clear communication can help determine patients’ readiness to employ potent therapies and/or can help assuage their fears about medication use. Physicians should recognize that patients using biologic therapies require a relatively modest time commitment, given the consistency of protocols and the likelihood that their condition can be stabilized for lengthy periods. Longer-term safety data are accumulating for these agents—some have now been in use for 10 years—and support the use of potent therapies for well-selected patients. Phase IV studies may help address some common and lingering concerns in this area. Although it is not yet clear that all systemic treatments for psoriasis will help decrease inflammatory comorbidities such as cardiovascular disease, the existing evidence is promising.

New Pathophysiologic Findings

Recent investigations of the genetic and immunological alterations associated with psoriasis have led to both a greater understanding of the pathophysiology of the disease and new targets for systemic treatment. Psoriasis is mediated and perpetuated by T-lymphocytes which, when activated by antigen-presenting cells, promote cytokine release and increased keratinocyte proliferation, inflammation and angiogenesis. A relatively new discovery is that upregulation of the cytokine interleukin (IL)-23, a dendritic cell response to the presence of micro-organisms in the skin, plays a primary role in the psoriatic process (Torti DC, Feldman SR. J Am Acad Dermatol 2007;57(6):1059-68). The main function of IL-23 is to stimulate the growth and survival of the T-cell subset Th-17, the level of which has been shown to be abnormally high in the blood of patients with psoriasis. Th-17 cells produce IL-17 and IL-22; the latter is a major contributor to keratinocyte proliferation. Animal studies have demonstrated that repeated injection of IL-23 produces skin lesions similar to psoriatic plaques. A recent report confirmed that polymorphisms in three genes involved in IL-23 signalling (p19, p40 and IL-23R) are among 10 genetic factors likely involved in susceptibility to psoriasis (Nair et al. Nat Genet 2009;41(2):199-204). The p19 and p40 protein subunits of IL-23 are markedly elevated in psoriatic lesions. Two additional genetic factors implicate tumour necrosis factor alpha (TNF-a).

New Agents Target IL-12/23

Two new biologic agents, the human monoclonal antibodies ABT-874 and ustekinumab, target the p40 subunit common to IL-12 and IL-23 as well as Th-17 cells. In phase II studies, ABT-874 has produced Psoriasis Area and Severity Index (PASI)-75 responses in up to 90% of patients receiving weekly or biweekly administration (Kimball et al. Arch Dermatol 2008;144(2):200-7). Ustekinumab was approved by Health Canada in December 2008 for the treatment of chronic moderate to severe psoriasis. A principal advantage of this agent is its 12-week interval between subcutaneous injections after two loading doses four weeks apart; its lengthy half-life promotes a long therapeutic response.

Two multicentre, phase III, double-blind, placebo-controlled studies confirmed the agent’s efficacy and safety. In the PHOENIX (Psoriasis Followed by Long-Term Extension) 1 trial, 766 adult patients with moderate to severe plaque psoriasis (PASI <u>></u>12 and BSA <u>></u>10%) were treated for up to 76 weeks (Leonardi et al. Lancet 2008;371(9625):1665-74) (Figure 1). After initial dosing at weeks 0 and 4, patients were treated every 12 weeks with ustekinumab 45 mg or 90 mg or placebo. The primary end point was the proportion of patients achieving PASI-75 at week 12. Secondary end points included Physician’s Global Assessment (PGA) of cleared or minimal disease and changes in Dermatology Life Quality Index (DLQI) at the same time point and time to loss of PASI-75 after 40 weeks in patients receiving maintenance treatment vs. placebo.

At week 12, 67.1% of patients receiving the 45-mg dose and 66.4% of those receiving the 90-mg dose of ustekinumab achieved PASI-75, compared with 3.1% of those receiving placebo (P<0.001) (Figure 1). Significantly more patients receiving active treatment also achieved PASI-50, -90 and -100 (P<0.001). At week 24, the point of maximum efficacy, 76.1% and 85% of the ustekinumab arms achieved PASI-75.

Figure 1.

During the randomized withdrawal phase of the study (weeks 40 to 76), patients receiving maintenance therapy were more likely to maintain their PASI-75 response than those assigned to discontinuation. Among patients in whom therapy was withdrawn, median time to loss of PASI-75 was 15 weeks, reinforcing the 12-week dosing schedule. There was no rebound of psoriasis after withdrawal of ustekinumab. Improvements in DLQI were significant with active treatment at week 12 and were sustained with maintenance treatment. Conversely, DLQI worsened in patients re-randomized to placebo.

The PHOENIX 2 trial evaluated whether ustekinumab administered every eight weeks would lead to a PASI-75 response in patients who had not responded adequately to treatment at 12-week intervals (Papp et al. Lancet 2008;371(9625):1675-84). In this study, 1230 patients were assigned to treatment with ustekinumab 45 mg or 90 mg or placebo. At week 28, patients achieving a partial response to therapy (PASI improvement of between 50% and 75%) were reassigned to dosing every 12 or eight weeks. Patients initially assigned to placebo were re-randomized to receive ustekinumab at weeks 12 and 16, then every 12 weeks thereafter. The study’s key end points were the same as those in PHOENIX 1; this trial also compared PASI-75 responses from baseline in patients receiving ustekinumab every 12 or every eight weeks during weeks 40 to 52.

In PHOENIX 2, 67% of patients receiving the 45-mg dose of ustekinumab and 76% of those receiving the 90-mg dose achieved PASI-75 at week 12 (Figure 1); these proportions were generally maintained through week 28. The study’s results confirmed that patients with a partial response to ustekinumab 90 mg who then received a dose every eight weeks were more likely than those continuing less frequent administration to achieve a PASI-75. The data suggest that it may be appropriate to try dose intensification in patients who achieve PASI-50 to -75 with an initial 90-mg dose. There were no similar findings with the lower dose of ustekinumab.

About 20% of the study population were deemed partial responders; these patients were more likely than responders to have a high body weight, long disease history, psoriatic arthritis and greater resistance to biologic agents. The investigators noted that partial responders to ustekinumab were more likely than responders to have developed antibodies to the drug (12.7% vs. 2%) and had serum drug levels two to three times lower than responders.

The PHOENIX studies suggest ustekinumab may be administered safely and is well tolerated over at least one year of use. Although there was no placebo comparison at one year, serious adverse events such as infection were no more common in treated patients after one year than after 12 weeks (Figure 2). Overall, adverse events were mild (nasopharyngitis and upper respiratory tract infection were most common) and did not require treatment adjustment. Injection site reactions were rare. Serious adverse events occurred in less than 2% of patients in each treatment group. There were no malignancies reported in PHOENIX 1; two cutaneous malignancies were reported in PHOENIX 2 (one in the placebo group). There were no cases of lymphoma, tuberculosis or demyelinating disease. In PHOENIX 1, maintenance therapy with ustekinumab did not increase the incidence of adverse events over that observed with interrupted treatment. In PHOENIX 2, more frequent dosing did increase adverse events. Observation of the PHOENIX patients continues, with three-year data to be available in May 2009 and five-year saf
years.

Figure 2.

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Biologics Compared

The recent 12-week, phase III ACCEPT trial comparing ustekinumab (45 mg or 90 mg at weeks 0 and 4) and etanercept (50 mg twice weekly) was the first comparative trial of biologic therapies in psoriasis. Many of the patients enrolled had experienced failure of conventional and systemic therapies. In this study, ustekinumab was more likely to produce a PASI-75 response: 68% and 74% of the ustekinumab arms, respectively, and 57% of the etanercept group achieved this primary end point (Figure 3). Similarly, a greater proportion of ustekinumab-treated patients (65% and 71%, respectively) were described by investigators as having minimal or cleared disease vs. 49% with etaner
ability findings were similar with the two agents.

Figure 3.

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Additional Management Considerations

Both the physical and psychological aspects of plaque psoriasis disease may impair patients’ quality of life. Through common genetic and immunologic pathways, the disease may heighten the risk of numerous other disorders associated with chronic inflammation. As such, a complete clinical picture is required for selection of therapy and dermatologists should ensure their patients with psoriasis are referred for follow-up by other specialists, as appropriate.