Skin disorders affect the world population and are often mostly defined by clinical parameters, but are generally not well understood at the cellular and biochemical levels. Psoriasis is a joint and skin disorder (at least four types of Psoriasis classified according to clinically observed symptoms of the skin) that affects 2–3% of the population, and is therefore one of the most common autoimmune diseases worldwide. As a chronic skin disorder characterized by epidermal hyperproliferation and dermal inflammation that vary in severity, from minor, localized patches to complete body coverage, psoriasis can be associated with other inflammatory conditions, such as psoriatic arthritis, inflammatory bowel disease and coronary artery disease. Many patients with psoriasis suffer from moderate to severe disease and report a substantial negative impact on their quality of life. Some estimates report a total annual direct and indirect costs of psoriasis of over US$11 billion. Missed work days account for 40% of the cost burden. About 10-15 percent of people with psoriasis also have psoriatic arthritis.
Psoriasis therapy has been directed at clearing the skin lesions and preventing their recurrence. Approximately 20% of patients with psoriasis have a very mild form of the disease where treatment with over the counter topical products are used. Treatment by physicians include topical agents, phototherapy, conventional oral systemic therapy and biologics. New stem cell-based therapeutics are being developed and offer a promising new avenue of therapy for this chronic, life-long disease.
Traditional therapies have included topical corticosteroids, such as clobetasol (Clobex; Galderma) and bethamethasone. These are the most prescribed treatments for most patients with mild to moderate psoriasis. Treatment with these compounds and subsequent withdrawl of treatment can lead to rebound, an aggressive recurrence of the condition. Other topical agents that are commonly used are 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). These treatments are generally considered to be safe, but have variable efficacies. Long-term use can potentially lead to adverse effects.
For moderate psoriasis that is unresponsive to topical therapy, phototherapy (UV radiation) is a cost-effective treatment option, but may require a considerable time commitment from the patient given the frequent physician office visits that are needed. System agents are used when psoriasis is refractory to topical therapy and phototherapy, or when the skin coverage is too extensive. Oral systemic agents include retinoids, methotrexate, cyclosporine and acitretine; they are efficacious, convenient, and inexpensive. However, using the oral systemics is limited by high levels of toxicity to the liver, kidneys and bone marrow, and their potential teratogenicity.
Research in the past decade has led to new “targeted therapies” based on how immune cells, such as T cells and dendrocytes, travel and use cytokine signaling to interact with one another. Two basic strategies are utilized: 1) anti-T cell , and 2) anti-cytokine therapies. 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 therapy. Six biologics have been approved so far.
Two biologics: 1) alefacept (Amevive; Astellas/Biogen) and 2) efalizumab (Raptiva/Xanelim; Genentech/Roche/Merck–Serono, target T cells that are involved in disease pathogenesis, and are not very efficacious. Efalizumab was withdrawn from the market due to an increase in the risk of progressive multifocal leukoencephalopathy.
Three other biologics: 1) adalimumab (Humira; Abbott), 2) etanercept (Enbrel; Amgen/Wyeth/Takeda), and 3) infliximab (Remicade; Centocor Ortho Biotech/Schering–Plough) , inhibit the activity of the pro-inflammatory cytokine tumour necrosis factor (TNF). Etanercept’s market position was stengthened through a first-to-market advantage and is currently the most widely prescribed biologic for psoriasis. The annual sales for this indication exceed $1.1 billion. Infliximab, administered by infusion in a physician’s office and typically prescribed to patients with the most severe disease, sold $250 million in 2008. Adalimumab, the third TNF inhibitor approved for psoriasis, has been gaining momentum in the market because of superior efficacy data from clinical trials and a more convenient dosing schedule, coupled with a pricing advantage. The sales of adalimumab for psoriasis was $785 million in 2008. TNF inhibitors, especially adalimumab, will likely benefit from the withdrawal of efalizumab.
Certolizumab (Cimzia; UCB), another TNF inhibitor, which is approved for Crohn’s disease and rheumatoid arthritis, demonstrated efficacy in Phase II psoriasis trials. However, this drug appears not to be in further development, possibly because of a saturated market. This may also be true of golimumab (Simponi; Centocor Ortho Biotech). Biosimilar versions of TNF inhibitors will likely enter the market and relieve cost pressures for these expensive drugs.
Ustekinumab (Stelara; Centocor Ortho Biotech/Janssen–Cilag), which inhibits the activity of interleukin-12 (IL-12) and IL-23, has shown strong overall efficacy and superiority to etanercept. Ustekinumab also offers durable efficacy and convenient dosing frequency (once every 12 weeks). Ustekinumab was approved in Europe in January 2009, and US approval is anticipated in late 2009 or early 2010.
Briakinumab is another agent that targets IL-12 and IL-23, (ABT-874; Abbott) that has completed Phase III studies (data are pending). Earlier trials of briakinumab showed impressive efficacy.
Products On The Horizon
Other products in development include stem cell-based theraputics for topical application. Studies of stem cells in the brain at the UCSD School of Medicine and other institutions, treating dementia for example, and stem cells in artificial skin, for wound healing, have demonstrated that the major effects of stem cells derive from their release of cytokines and growth factors into the area of tissue to be repaired. Thus, in these treatments, live stem cells are releasing cytokines and growth factors into the area to be repaired as a topical application. In recent pilot studies evolving from the aforementioned stem cell studies, formulation of the stem cell-released cytokines and growth factors into a topical product have shown good efficacy with no side effects when treating psoriasis.