Psoriasis is a chronic skin disorder characterized by epidermal hyperproliferation and dermal inflammation that vary in severity, from minor, localized patches to complete body coverage. It affects approx2–3% of the population, making it one of the most prevalent autoimmune diseases worldwide, and can be associated with other inflammatory conditions, such as psoriatic arthritis, inflammatory bowel disease and coronary artery disease. Approximately one-third of patients with psoriasis suffer from moderate to severe disease (Table 1) and report that this has a substantial negative impact on their quality of life. According to the National Psoriasis Foundation, USA, total annual direct and indirect costs of psoriasis are over US$11 billion, with missed work days accounting for 40% of the cost burden.
The goal of psoriasis therapy is to clear the skin lesions and prevent their recurrence. An estimated 20% of patients with psoriasis have a very mild form of disease and rely on over the counter topical products. Physician-prescribed therapies include topical agents, phototherapy, conventional oral systemic therapy and biologics1 (Fig. 1).
Topical corticosteroids, such as clobetasol (Clobex; Galderma) and bethamethasone, are the mainstay of treatment for most patients with mild to moderate psoriasis. Other commonly used topical agents include vitamin D3 analogues, such as calcipotriene (Davonex/Daivonex; Leo Pharma/Warner Chilcott); retinoids, such as tazarotene (Tazorac/Zorac; Allergan); and a fixed-dose combination of calcipotriene and bethamethasone (Taclonex/Xamiol/Dovobet; Warner Chilcott) (Fig. 2). These treatments have variable efficacies. They are generally considered to be safe, although long-term use could lead to adverse effects.
Phototherapy is a cost-effective treatment option for moderate psoriasis that is unresponsive to topical therapy, but could require a considerable time commitment from the patient, owing to the frequent physician office visits that are needed. When psoriasis is refractory to topical therapy and phototherapy, or skin coverage is too extensive, systemic agents are used1. Conventional oral systemic agents — retinoids, methotrexate, cyclosporine and acitretine — are effective, convenient to use and inexpensive. However, their use is limited by high levels of toxicity to the liver, kidneys and bone marrow, as well as by teratogenicity.
Compared with the conventional systemic agents, biologics that target specific aspects of the immune system aim to offer improved safety and tolerability, thereby enabling longer-term therapy1. Six biologics have been approved so far.
Two of these biologics — alefacept (Amevive; Astellas/Biogen) and efalizumab (Raptiva/Xanelim; Genentech/Roche/Merck–Serono) — target T cells that are involved in disease pathogenesis, but have been niche agents owing to modest efficacy. Efalizumab was recently withdrawn from the market because it was found to increase the risk of progressive multifocal leukoencephalopathy.
Three other biologics — adalimumab (Humira; Abbott), etanercept (Enbrel; Amgen/Wyeth/Takeda) and infliximab (Remicade; Centocor Ortho Biotech/Schering–Plough) — inhibit the activity of the key pro-inflammatory cytokine tumour necrosis factor (TNF). Of the three, etanercept clearly gained from its first-to-market advantage and is currently the most widely prescribed biologic for psoriasis. Its annual sales for this indication exceed $1.1 billion (Fig. 2). Infliximab, which is administered by infusion in a physician's office and is typically prescribed to patients with the most severe disease, had sales of $250 million for psoriasis in 2008. Adalimumab was the third TNF inhibitor to be approved for psoriasis, but has been gaining momentum in the market against etanercept, owing to superior efficacy data from clinical trials (Psoriasis Area and Severity Index (PASI) 75: 71–78% and 32–47%, respectively), a more convenient dosing schedule and a modest pricing advantage. The sales of adalimumab for psoriasis reached $785 million in 2008. TNF inhibitors stand to benefit from the withdrawal of efalizumab, with adalimumab probably capturing the greatest market share.
Another TNF inhibitor, certolizumab (Cimzia; UCB), which is approved for Crohn's disease and rheumatoid arthritis, showed good efficacy in Phase II psoriasis trials2. However, no development of this agent for psoriasis has been reported since 2007, probably because it would be hard to differentiate a fourth TNF inhibitor within this indication. The same issue might apply to golimumab (Simponi; Centocor Ortho Biotech), which has recently been approved for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. In the future, it is likely that biosimilar versions of TNF inhibitors will enter the market and relieve cost pressures for these expensive drugs.
Finally, ustekinumab (Stelara; Centocor Ortho Biotech/Janssen–Cilag), which inhibits the activity of interleukin-12 (IL-12) and IL-23, has shown strong overall efficacy (PASI 75: 67–76%) and superiority to etanercept (PASI 75: 68–74% versus 57%)3. Ustekinumab also offers a durable response (PASI 75: 84% at 76 weeks) and convenient dosing frequency (once every 12 weeks, compared with adalimumab at twice per month). Although ustekinumab is expected to have a strong market uptake, it is unlikely to displace TNF inhibitors as first-line therapy in the near future, as its long-term safety is currently unknown. It was approved in Europe in January 2009, and US approval is anticipated in late 2009.
A second agent that targets IL-12 and IL-23, briakinumab (ABT-874; Abbott)2, has completed Phase III studies (data are pending). In earlier trials, briakinumab showed impressive efficacy — a PASI 75 of up to 93%. If these results are reproduced in the Phase III trial, upon approval briakinumab could pose serious competition to ustekinumab.
Most of the compounds for psoriasis treatment that are in late-stage development fall into existing drug classes (Table 2). Among the more intriguing approaches are oral therapies that could offer safety improvements and cost savings over biologics. Celgene's apremilast is an oral agent with several targets, including phosphodiesterase 4, TNF, IL-2, IL-6, IL-17 and IL-23. Currently, it is in Phase IIb studies in moderate to severe plaque-type psoriasis, with results expected in the first half of 2010. However, in earlier studies, apremilast seemed to be less effective than injectable TNF inhibitors.
Topical agents with novel mechanisms of action are also of interest. Anacor Pharmaceuticals' AN2728 — a boron-containing small molecule formulated as a topical ointment — has a target profile similar to that of apremilast, and may avoid many of the safety issues associated with systemic agents. Although that might be the case, a topical agent is most likely to be limited to patients with mild psoriasis that is restricted in terms of lesion area.
The value of the psoriasis market is constrained by the dominance of generic and non-prescription treatments, which are used by most patients. Wide adoption of biologics has been limited by both high cost and long-term safety concerns. Nevertheless, 68% of the $3.5 billion global psoriasis market is captured by biologic therapies; topical agents and conventional systemic drugs account for approx25% and approx7%, respectively. Approval of new biologics could drive market growth; however, increasing reimbursement pressures are likely to limit substantial market expansion.
* Clinical trials.gov
* The National Psoriasis Foundation
1. Menter, A. et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. J. Am. Acad. Derm. 58, 826–850 (2008)
2. Rozenblit, M. & Lebwohl, M. New biologics for psoriasis and psoriatic arthritis. Derm. Therapy. 22, 56–60 (2009).
3. Reich, K. et al. Ustekinumab. Nature Rev. Drug Discov. 8, 355–356 (2009).
1. Irena Melnikova, Ph.D., is a Principal at TVM Capital, 101 Arch Street, Boston, Massachusetts 02110, USA. Email: firstname.lastname@example.org