Psoriasis market and current treatments
According to a 2016 Global Report on Psoriasis issued by the World Health Organization, the prevalence of psoriasis in countries ranges between 0.09% and 11.43%, making psoriasis a serious global problem with at least 100 million individuals affected worldwide. According to LeadDiscovery, in 2009, over 4.5 million prescriptions were written for patients with psoriasis in the U.S., with approximately 3.9 million of these prescriptions written for topical therapies.
Patients suffering from severe psoriasis can benefit from antibody therapeutics, such as etanercept or adalimumab. These antibodies target TNF, a cytokine that plays a central role in the inflammation underlying psoriasis. When injected, the antibodies bind to TNF, diminishing TNF’s ability to act as an inflammatory signal. Patients with limited disease, or mild to moderate psoriasis, can be treated with topical or oral anti-inflammatory therapeutic agents. These patients are generally not treated with systemic anti-TNF antibodies due to adverse health risks. According to the American Academy of Dermatology, patients with limited skin disease should not automatically be treated with systemic treatments if they do not improve, because treatment with systemic therapy may carry more risk than the disease itself.
Accordingly, topically applied agents, such as corticosteroids, are widely used to treat mild to moderate psoriasis. Unlike antibodies that target a specific pathway to treat psoriasis, topical therapies generally have a non-specific mechanism of action, which may cause skin thinning, skin irritation, and other side effects. Moreover, many of these therapies become less effective at treating the disease over time as patients become refractory to treatment. Findings from National Psoriasis Foundation surveys conducted between 2003 and 2011 indicate that 52.3% of patients with psoriasis were dissatisfied with their treatment.
We believe there is an unmet medical need in mild to moderate psoriasis for a locally administered therapeutic that combines the specificity of antibodies with the convenience of topical corticosteroids without the side effects of either class of therapeutics. To date, the skin has proven to be a barrier to the penetration of many potential therapies. Some approaches for delivering oligonucleotides directly into the skin require injections, which may be uncomfortable and painful.
AST-005 is intended to be administered locally as a topically applied gel to psoriatic lesions. We developed AST-005 to enter into cells of the epidermis and dermis and modulate the expression of TNF.
Clinical success of systemically delivered anti-TNF antibodies has validated TNF as a clinically relevant target for psoriasis. TNF is an important trigger and mediator of inflammatory responses. Excessive TNF production in the skin causes keratinocyte and T-cell proliferation as well as immune cell infiltration, which results in the formation of psoriatic lesions.
Preclinical development of AST-005
We gathered experimental evidence of the biological activity of AST-005 in both healthy and psoriatic human skin samples prior to undertaking a Phase 1 clinical trial. As a consequence, we believe we had a deeper understanding of how AST-005 would perform during clinical trials than would be ordinarily possible with traditional therapeutic development. Data from our preclinical studies demonstrated that AST-005 penetrates into, and modulates the production of TNF in, both healthy and psoriatic human skin after topical application. We believe we had preliminarily demonstrated the intended therapeutic mechanism of action of AST-005 in the tissue of interest in advance of a Phase 1 clinical trial. We intend to use this model when developing other gene regulatory SNA compounds.
We also examined AST-005 in a mouse model of psoriasis known as the imiquimod model. AST-005 was applied topically in an ointment. Histological and biomarker results showed that AST-005 prevents the development