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The psoriasis and atopic dermatitis markets have historically been dominated by topical steroids, vitamin D analogues, and calcineurin inhibitors; all of which are over 20 years-old. There is room for improved efficacy and all three mechanisms suffer from local toleration issues such as skin thinning and stretch marks, application site irritation, and redness. There is also a potential risk of systemic adverse effects through inhibition of the hypothalamic-pituitary axis and alterations in calcium metabolism. Indeed, none of these treatments can be used for more than 8 weeks, limiting their utility in treating a usually chronic, relapsing disease.
For more severe disease, systemic agents such as steroids, methotrexate, and cyclosporine are used, either alone, or in combination with the new biological agents that have recently entered the market. These target specific inflammatory mechanisms, and, in some cases, have been extremely successful. Pfizer’s Enbrel, a TNF inhibitor, reached $1.3 billion in sales for psoriasis in 2010.1 And Abbott’s Humira, a TNFα monoclonal antibody, has been approved for multiple indications, feeding sales of $6.5 billion in 20102—sales for psoriasis were $785 million in 2008.3 Oral kinase inhibitors have recently been investigated for psoriasis with Pfizer’s tofacitinib, a JAK inhibitor, showing promise.
As promising as these approaches are, they can cause side-effects when systemic circulation is utilized for delivery of pharmacology to the skin. These compounds also target general or specific inflammatory pathways, rather than the keratinocytes that are responsible for the skin plaques in psoriasis and the inflammatory process and itch in atopic dermatitis.4
Applying medication directly to diseased skin can focus pharmacology where it is needed and minimize or eliminate systemic pharmacology where it is not, improving the therapeutic index—the balance between efficacy and safety.
Kinase inhibitors offer a novel approach to the treatment of psoriasis, particularly as kinases play key roles in keratinocyte hyperproliferation. TrkA, for example, is the high-affinity receptor for NGF. NGF is released in increasing amounts by proliferating keratinocytes, and has been shown to induce proliferation.5 Through the induction of TrkA auto-phosphorylation and activation of the MAPK cascade, NGF increases keratinocyte proliferation. In psoriatic skin, TrkA mRNA is expressed in all epidermal layers, rather than just the epidermis,6 while NGF is also expressed three- to fourfold higher in psoriatic plaques.7
A topical TrkA kinase inhibitor, CT327, is being developed by Creabilis using its Low Systemic Exposure (LSE) technology. CT327 has shown early efficacy in Phase 2 clinical trials in psoriasis and atopic dermatitis comparable to current treatment options such as steroids.
However, unlike steroids, CT327 appears to be well-tolerated on application to the skin. In addition, blood levels of CT327 cannot be measured, which has led to few or no adverse events of a systemic nature. This suggests that CT327 shouldn’t have some of the drawbacks of existing topical agents and the systemic side effects of the biologics. CT327 could thus offer patients an effective, but safer treatment option.
CT327 is currently in Phase 2b trials to optimize efficacy and dose in psoriasis. A Phase 2b study in atopic dermatitis is planned to begin at the end of 2012.
References
1. Decision Resources. The Psoriasis Drug Market Will Increase From $3.9 Billion In 2010 To More Than $7.4 Billion In 2020. Available from https://decisionresources.com/News-and-Events/Press-Releases/Psoriasis-111711. Accessed on May 30, 2012.
2. Abbott. Financial Review Part 1. Available from https://www.abbott.com/static/content/microsite/annual_report/2010/16_review1.html. Accessed on May 30, 2012.
3. Melnikova I. Psoriasis Market. Nat Rev Drug Discov. 2009;8(10):767-8.
4. Pincelli C, et al. Expression and function of nerve growth factor and nerve growth factor receptor on cultured keratinocytes. J Invest Dermatol. 1994; 103(1):13-8.
5. Pincelli C. Nerve growth factor and keratinocytes: a role in psoriasis. Eur J Dermatol. 2000; 10(2):85-90.
6. Raychaudhuri SP, et al. Psoriatic keratinocytes express high levels of nerve growth factor. Acta Derm Venereol. 1998;78(2):84-6.
7. Fantini F, et al. Nerve growth factor is increased in psoriatic skin. J Invest Dermatol. 1995;105(6):854-5.
Filed Under: Drug Discovery
